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"Latar Belakang: Breast Cancer Stem Cells (BCSC) merupakan populasi selkanker payudara yang mempunyai sifat sel punca. BCSC menjaga stabilitas tumordengan menginisiasi pembentukan populasi sel kanker baru serta memberikankekebalan terhadap terapi. BCSC dapat berinteraksi dengan lingkungan mikrotumor yang melepaskan berbagai sitokin dan growth factor, termasuk TGF-β1.Melalui mekanisme autoinduksi, TGF-β1 dapat meningkatkan produksi TGF-β1endogen dan pensinyalan autokrinnya. Pensinyalan autokrin TGF-β1 dapatmeningkatkan pengaruh tumor promotor TGF-β1 dalam perkembangan kankermelalui penguatan karakter kepuncaan dan sifat tumorigenik. Penelitian inibertujuan untuk enganalisis efek pemberian TGF-β1 rekombinan manusia pada selpunca kanker payudara (aldehyde dehydrogenase positive, ALDH+) terhadapekspresi marker kepuncaan melalui pensinyalan autokrin TGF-β1. Sebagaipembanding digunakan kanker payudara subtipe triple negative (TNBC).Metode: BCSCs manusia (ALDH+) dan TNBC (MDA-MB-231) dikultur dalamDulbecco's Modified Eagle Medium/Nutrient Mixture F12/HG (DMEM F12/HG)dengan suplemen 0,1 ng/ml protein rekombinan TGF-β1 manusia (rhTGF-β1)selama periode 1, 2 dan 4 jam. Medium kultur kemudian diganti dengan DMEMF12/HG tanpa serum selama 24 jam. Tingkat ekspresi mRNA reseptor TGF-β tipe1 (TβR1), TGF-β1, faktor transkripsi pengikat oktamer 4 (OCT4), dan anggota A1keluarga aldehida dehidrogenase 1 (ALDH1A1) dianalisis menggunakan real timereverse transcriptase polymerase chain reactions (RT-qPCR). Kadar protein TGF-β1 dalam media kultur ditentukan dengan menggunakan enzyme-linkedimmunosorbent assay (ELISA). Sifat tumorigenik sel diuji dengan ujimammosphere forming unit (MFU assay).Hasil: Tingkat ekspresi mRNA dan protein TGF-β1 BCSC setelah perlakuantampak meningkat namun tidak pada TNBC. mRNA TβR1 BCSCs meningkat padaperiode perlakuan 1 dan 2 jam, sedangkan pada TNBC hanya pada periode 1 jam.Penanda kepuncaan ALDH1A1 dan OCT4 tampak meningkat pada BCSC namuntidak pada TNBC. Uji MFU menunjukkan sifat tumorigenik kedua kelompok selterutama pada periode perlakuan 2 jam tampak meningkat.Kesimpulan: Perlakuan TGF-β1 dalam konsentrasi rendah dan dalam waktusingkat memicu autoinduksi pada BCSCs yang menyebabkan peningkatan ekspresigen kepuncaan melalui pensinyalan autokrin. Sedangkan pada TNBC, peningkatanekspresi marker kepuncaan tidak terjadi. Namun demikian, sifat tumorigenik BCSCdan TNBC tetap meningkat.

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Background: Breast Cancer Stem Cells (BCSC) is a population of breast cancer

cells that have stem cell characteristics. BCSCs maintain tumor stability by

initiating the formation of new cancer cell populations and providing resistance to

therapy. BCSCs can interact with the tumor microenvironment which releasing

various cytokines and growth factors, including TGF-β1. Through the

autoinduction mechanism, TGF-β1 can increase endogenous TGF-β1 production

and autocrine signaling. TGF-β1 autocrine signaling can increase the tumor

promoter role of TGF-β1 in cancer development by enhancing the stemness and

tumorigenic properties. This study aims to analyze the effect of Human TGF-β1

recombinant protein treatment to breast cancer stem cells (aldehyde dehydrogenase

positive, ALDH+) on the expression of stemness marker through TGF-β1 autocrine

signaling. Triple negative breast cancer (TNBC) was used as a comparison.

Methods: Human BCSCs (ALDH+) and TNBC (MDA-MB-231) were cultured in

Dulbecco's Modified Eagle Medium/Nutrient Mixture F12/HG (DMEM F12/HG)

with 0.1 ng / ml recombinant protein of human TGF-β1 supplementation (rhTGF-

β1) over 1, 2 and 4 hour periods. The culture medium was then replaced with

DMEM F12/HG serum-free for 24 hours. The expression levels of the TGF-β

receptor type 1 (TβR1), TGF-β1, octamer-binding transcription factor 4 (OCT4),

and members of the A1 family of aldehyde dehydrogenase 1 (ALDH1A1) mRNA

were analyzed using real time reverse transcriptase polymerase chain reactions

(RT-qPCR). TGF-β1 protein levels in conditioned medium were determined using

an enzyme-linked immunosorbent assay (ELISA). The tumorigenic properties of

cells were tested by the mammosphere forming unit (MFU) assay.

Results: The expression level of mRNA and TGF-β1 BCSC protein after treatment

appeared to be increased but not in TNBC. mRNA TβR1 BCSCs increased in the

treatment period of 1 and 2 hours, whereas in TNBC only in the 1 hour period. The

markers of ALDH1A1 and OCT4 expression appeared to be increased in BCSC but

not in TNBC. The MFU test showed that the tumorigenic properties of both cell

groups, especially in the 2 hour treatment period, appeared to be increasing.

Conclusion: Treatment of TGF-β1 in low concentrations and in a short time

triggered autoinduction of BCSCs and leads to the increased expression of stemness

genes marker via autocrine signaling. Whereas in TNBC, this increase in the

expression of the stemness markers did not occur. However, the tumorigenic nature

of BCSC and TNBC continues to increase."

"ABSTRAKPelipatan protein merupakan hal penting dalam pembentukan struktur native protein dan fungsi biologisnya. Kesalahan pelipatan protein dapat menyebabkan penyakit seperti Alzheimers dan fibrosis kistik. Struktur native protein Transforming growth factor b3 (TGF-b3) berbentuk dimer yang diperoleh dari hasil pelipatan monomer identik. Struktur native TGF-b3 dapat diperoleh dari rekombinan TGF-b3 dari E.coli dengan beberapa perlakuan kimia, namun proses ini cenderung membentuk badan iklusi yang mengandung protein non-aktif. Pada umumnya, protein yang terlipat dengan benar menjadi bentuk native merupakan protein yang aktif. Oleh karena itu diperlukan simulasi dinamika molekuler untuk mengetahui mampukah monomer protein TGF-b3 melakukan selffolding. Simulasi dinamika molekuler protein menggunakan perangkat Amber dilakukan pada rantai asam amino struktur monomer protein TGF-b3 dengan identitas PDB 1TGJ. Proses simulasi dilakukan selama 9 μs menggunakan parameter gabungan Amber forcefield ff14SBonlysc, GBNeck2, dan mbondi3 dalam sistem yang tidak menghitung interaksi atom dengan air. Hasil simulasi diperoleh struktur yang berbeda dari struktur monomer kristal protein pada PDB. Rata-rata RMSD dari perbandingan kedua struktur didapatkan kurang lebih 15-16 Å dengan RMSD terendah yakni 14,0479 Å. Dari simulasidinamika molekuler yang dilakukan dengan pendekatan all atom dalam implisit solven, diperoleh struktur monomer non-native protein TGF-b3

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ABSTRACTProtein folding has an important role in the formation of native structure and their biological functions. Incorrect folding can cause diseases such as Alzheimer's and cystic fibrosis. The structure of Transforming growth factor b3 (TGF-b3), in the form of dimers, obtained from folded monomer. Its native structure can be obtained from recombinant TGF-b3 from E. coli when given several chemical treatments, but prone to be misfolded therefore a molecular dynamics simulation is needed to determine whether self-folding of monomer TGF-b3 can be done. Molecular dynamics simulations of protein using Amber software were performed on amino acid chains of monomer TGF-b3 from PDB, the identity is 1TGJ. The simulation process is carried out for 9 μs using a combined parameter of Amber forcefield ff14SBonlysc, GBNeck2, and mbondi3 at an implicit water environment. Unfortunately, the structure obtained from the simulation was different from its monomer crystal structure. The average RMSD we got in the comparison between result structure and monomer crystal structures was approximately 15-16 Å with the lowest RMSD was 14,0479 Å. From the molecular dynamics simulation carried out with the approach of all atoms in implicit water, the non-native structure of monomer TGF-b3 protein was obtained."

"Latar Belakang : Kanker payudara merupakan salah satu kanker tersering pada wanita. Saat ini keberhasilan pengobatan terhadap kanker payudara masih rendah selain karena progesifitas tumor, tumor juga kadang bersifat resisten terhadap pengobatan, adanya metastasis dan meningkatnya agresivitas. Penelitian menunjukkan adanya peranan dari subset populasi sel punca kanker payudara (breast cancer stem cells, BCSC) yang menyokong pada sifat keganasan kanker ini. Selain Oct4 sebagai penanda kepuncaan sel, salah satu penanda yang dipakai dalam menyortir BCSC adalah aldehyde dehydrogenase (ALDH), dan dari 19 subfamili ALDH diteliti isoform ALDH1A1 dan ALDH1A3 yang dominan berperan pada BCSC. Selain itu adanya kondisi hipoksia turut mendukung menyebabkan kegasanan kanker payudara meningkat. Penelitian ini bertujuan untuk melihat pengaruh hipoksia pada ekspresi mRNA ALDH1A1 dan ALDH1A3 dan hubungannya dengan kepuncaan dan ketahanan hidup sel punca kanker payudara ALDH+. Metode: Sampel menggunakan kultur sel BCSC ALDH dan sel MCF-7. Dilakukan inkubasi hipoksia (O2 1) dan normoksia (O2 20) selama 6, 24 dan 48 jam kemudian dilakukan analisis ekspresi HIF1, ALDH1A1, ALDH1A3 dan Oct4. Selanjutnya dilakukan analisis viabilitas dan pengukuran mammosphere forming unit (MFU). Hasil : Studi menunjukkan kondisi hipoksia menyebabkan peningkatan ekspresi ALDH1A3 pada sel BCSC ALDH sedangkan ALDH1A1 mengalami penurunan ekspresi dibandingkan dengan sel normoksia, sementara pada sel MCF-7 terjadi hal sebaliknya. Ekspresi Oct4 mengalami peningkatan pada awal hipoksia (6 jam) kemudian menurun. Terjadi penurunan MFU, sedangkan ketahanan hidup sel tetap stabil. Kesimpulan : Kondisi hipoksia bisa menyebabkan penurunan sifat kepuncaan pada sel BCSC ALDH ditinjau dari penanda self-renewal, pluripotensi dan tumorigenitas, tetapi ketahanan hidup sel tetap stabil.

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Background: Breast cancer is one of frequent cancer-related disease among women. Complete successful therapy to breast cancer was still a big challenge considering the tumour progression, therapy resistancy, metastatic ability and increasing aggressivity. Studies shown that breast cancer stem cells (BCSC) subset were involved to maintain the malignancy. Besides the well-known cell stemness marker Oct4, researchers also suggested aldehyde dehydrogenase (ALDH) as a marker of BCSC, in which ALDH1A1 and ALDH1A3 believed to play dominant role. In addition, tumour hypoxia might also support increasing malignancy. This study aimed to analyze the expressions of ALDH1A1 and ALDH1A3 mRNA and their correlation with stemness properties and cell survival of hypoxic BCSC ALDH+.

Method(s): Samples were obtained using BCSC ALDH and MCF-7 cells. The cells then being treated with hypoxia (O2 1) and normoxia (O2 20) conditions for 6, 24 and 48 hours respectively. We also measured the cells survival and mammosphere forming unit (MFU) capability to analyze cell proliferation.

Result(s): Our study showed that ALDH1A3 in BCSC ALDH hypoxia cells was expressed at significantly higher level but ALDH1A1 was at lower level compared to their respective normoxia cells, while we found the opposite results in MCF-7 cells. Oct4 expression was increased at early hypoxia (6 hours) then declined shortly. MFU was reduced but cells survival remained stable.

Conclusion(s): Hypoxic condition decreased the stemness properties of BCSC ALDH considering the self renewal, pluripotency, and tumorigenicity markers. However, cells survival remained stable."

"[ABSTRAKKanker payudara adalah penyakit multifaktor yang mengakibatkan insiden kematian wanita tertinggi di dunia. Pengobatan kanker payudara berupa pembedahan, radioterapi, dan kemoterapi memiliki efek samping sehingga perlu pengobatan alternatif, salah satunya menggunakan bahan herbal. Daun sirsak (Annona muricata Linn) dilaporkan memiliki efek antitumor dan sitotoksik, tetapi penelitian in vivo terhadap kanker payudara masih sedikit, dibutuhkan penelitian lanjut mengenai efektivitas dan jalur penghambatan daun sirsak terhadap berbagai kanker. Penelitian ini bertujuan untuk mengetahui daya hambat dan dosis efektif ekstrak metanol daun sirsak (Annona muricata Linn) terhadap pertumbuhan tumor payudara mencit C3H secara in vivo. Sebanyak 30 ekor mencit galur C3H yang ditransplan dengan tumor payudara dari mencit C3H donor bertumor, dibagi dalam 5 kelompok perlakuan, yaitu kontrol negatif hanya diberi pelarut CMC 0,5%, kontrol positif diberi doksorubisin, kelompok pemberian ekstrak daun sirsak dosis 15, 30, dan 45 mg/kg BB. Setiap mencit dicekok ekstrak daun sirsak 0,2 cc per hari selama 21 hari, sedangkan kelompok kontrol positif diberikan doksorubisin secara intra vena 0,03 μg/20g BB seminggu sekali selama 21 hari. Panjang dan lebar tumor diukur di awal dan seminggu sekali selama perlakuan untuk mendapatkan data volume tumor. Pada akhir penelitian mencit dinekropsi, tumor mencit ditimbang dan dilakukan pewarnaan AgNOR untuk diukur aktivitas proliferasi sel. Hasil uji Anova menunjukkan perbedaan yang bermakna (p=0,007) antar perlakuan terhadap volume tumor akhir dan terhadap aktivitas proliferasi (p=0,001). Uji Kruskal Wallis terhadap berat tumor menunjukkan tidak ada perbedaan yang bermakna antar perlakuan (p=0,03). Hasil uji korelasi Spearman secara bermakna (p=0,03) menunjukkan ada korelasi positif antara aktivitas proliferasi sel dengan pertumbuhan volume tumor dengan kekuatan korelasi yang lemah (r=0,39). Disimpulkan bahwa ekstrak metanol daun sirsak (Annona muricata Linn) dapat menghambat laju pertumbuhan volume tumor dan aktivitas proliferasi sel kanker payudara mencit C3H dan optimum penghambatan pada dosis 30 mg/kg

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ABSTRACTBB.;Breast cancer is a multifactor disease that has been a leading cause of woman?s mortality. Treatments for breast cancer such as surgery, radiotherapy, and chemotherapy have their own side effects, so that alternative treatments such as herbal medicine are needed. Soursop leaf (Annona muricata Linn) has been reported to have antitumor and cytotoxic effects, but only few conducted in vivo, an advanced research is needed to find the effectiveness and the inhibition pathway of the soursop leaf. The purpose of this research is to find out the inhibition capacity and the effective dose of soursop leaf methanol extract (Annona muricata Linn) against the development of C3H mice?s breast cancer in vivo. There were thirty mice of C3H strain which were transplanted with breast tumor and they were divided into five groups consisting of negative control group which was given only solvent CMC 0.5%, a positive control group which was given doxorubicin, a dose group of 15 mg/kg BB, a dose group of 30 mg/kg BB, and a dose group of 45 mg/kg BB. Each mouse was given 0,2 cc soursop leaf extract every day for 21 days while the positive control group was given doxorubicin 0,03 μg/20 gram BB once a week for 21 days intravenously. The length and the width of the tumor were measured at the beginning and also measured once a week during the experiment process to gain the data of the tumor volume. At the end of the research, the tumor of the mice was lifted and weighed and it was stained by AgNOR to measure the proliferation activity of the cell. The Anova result showed that there was a significant difference (p=0,007) between treatment against the development of tumor which was marked by the decrease of the tumor volume and proliferation activity (p=0,001). The Kruskal Wallis result showed that there was no significant difference (p<0,33) in the tumor weight. Spearman correlation study significantly (p=0,03) indicated that there was a positive correlation between the cell proliferation activity and the growth of the tumor but in a weak correlation (r=0,39). Therefore, it could be concluded that the methanol extract of soursop leaf (Annona muricata Linn) can inhibit the growth rate of tumor volume as well as the proliferation activity of the breast cancer cell of C3H mice and it worked optimally at 30 mg/kg BB dose.;Breast cancer is a multifactor disease that has been a leading cause of woman?s mortality. Treatments for breast cancer such as surgery, radiotherapy, and chemotherapy have their own side effects, so that alternative treatments such as herbal medicine are needed. Soursop leaf (Annona muricata Linn) has been reported to have antitumor and cytotoxic effects, but only few conducted in vivo, an advanced research is needed to find the effectiveness and the inhibition pathway of the soursop leaf. The purpose of this research is to find out the inhibition capacity and the effective dose of soursop leaf methanol extract (Annona muricata Linn) against the development of C3H mice?s breast cancer in vivo. There were thirty mice of C3H strain which were transplanted with breast tumor and they were divided into five groups consisting of negative control group which was given only solvent CMC 0.5%, a positive control group which was given doxorubicin, a dose group of 15 mg/kg BB, a dose group of 30 mg/kg BB, and a dose group of 45 mg/kg BB. Each mouse was given 0,2 cc soursop leaf extract every day for 21 days while the positive control group was given doxorubicin 0,03 μg/20 gram BB once a week for 21 days intravenously. The length and the width of the tumor were measured at the beginning and also measured once a week during the experiment process to gain the data of the tumor volume. At the end of the research, the tumor of the mice was lifted and weighed and it was stained by AgNOR to measure the proliferation activity of the cell. The Anova result showed that there was a significant difference (p=0,007) between treatment against the development of tumor which was marked by the decrease of the tumor volume and proliferation activity (p=0,001). The Kruskal Wallis result showed that there was no significant difference (p<0,33) in the tumor weight. Spearman correlation study significantly (p=0,03) indicated that there was a positive correlation between the cell proliferation activity and the growth of the tumor but in a weak correlation (r=0,39). Therefore, it could be concluded that the methanol extract of soursop leaf (Annona muricata Linn) can inhibit the growth rate of tumor volume as well as the proliferation activity of the breast cancer cell of C3H mice and it worked optimally at 30 mg/kg BB dose.;Breast cancer is a multifactor disease that has been a leading cause of woman?s mortality. Treatments for breast cancer such as surgery, radiotherapy, and chemotherapy have their own side effects, so that alternative treatments such as herbal medicine are needed. Soursop leaf (Annona muricata Linn) has been reported to have antitumor and cytotoxic effects, but only few conducted in vivo, an advanced research is needed to find the effectiveness and the inhibition pathway of the soursop leaf. The purpose of this research is to find out the inhibition capacity and the effective dose of soursop leaf methanol extract (Annona muricata Linn) against the development of C3H mice?s breast cancer in vivo. There were thirty mice of C3H strain which were transplanted with breast tumor and they were divided into five groups consisting of negative control group which was given only solvent CMC 0.5%, a positive control group which was given doxorubicin, a dose group of 15 mg/kg BB, a dose group of 30 mg/kg BB, and a dose group of 45 mg/kg BB. Each mouse was given 0,2 cc soursop leaf extract every day for 21 days while the positive control group was given doxorubicin 0,03 μg/20 gram BB once a week for 21 days intravenously. The length and the width of the tumor were measured at the beginning and also measured once a week during the experiment process to gain the data of the tumor volume. At the end of the research, the tumor of the mice was lifted and weighed and it was stained by AgNOR to measure the proliferation activity of the cell. The Anova result showed that there was a significant difference (p=0,007) between treatment against the development of tumor which was marked by the decrease of the tumor volume and proliferation activity (p=0,001). The Kruskal Wallis result showed that there was no significant difference (p<0,33) in the tumor weight. Spearman correlation study significantly (p=0,03) indicated that there was a positive correlation between the cell proliferation activity and the growth of the tumor but in a weak correlation (r=0,39). Therefore, it could be concluded that the methanol extract of soursop leaf (Annona muricata Linn) can inhibit the growth rate of tumor volume as well as the proliferation activity of the breast cancer cell of C3H mice and it worked optimally at 30 mg/kg BB dose.;Breast cancer is a multifactor disease that has been a leading cause of woman?s mortality. Treatments for breast cancer such as surgery, radiotherapy, and chemotherapy have their own side effects, so that alternative treatments such as herbal medicine are needed. Soursop leaf (Annona muricata Linn) has been reported to have antitumor and cytotoxic effects, but only few conducted in vivo, an advanced research is needed to find the effectiveness and the inhibition pathway of the soursop leaf. The purpose of this research is to find out the inhibition capacity and the effective dose of soursop leaf methanol extract (Annona muricata Linn) against the development of C3H mice?s breast cancer in vivo. There were thirty mice of C3H strain which were transplanted with breast tumor and they were divided into five groups consisting of negative control group which was given only solvent CMC 0.5%, a positive control group which was given doxorubicin, a dose group of 15 mg/kg BB, a dose group of 30 mg/kg BB, and a dose group of 45 mg/kg BB. Each mouse was given 0,2 cc soursop leaf extract every day for 21 days while the positive control group was given doxorubicin 0,03 μg/20 gram BB once a week for 21 days intravenously. The length and the width of the tumor were measured at the beginning and also measured once a week during the experiment process to gain the data of the tumor volume. At the end of the research, the tumor of the mice was lifted and weighed and it was stained by AgNOR to measure the proliferation activity of the cell. The Anova result showed that there was a significant difference (p=0,007) between treatment against the development of tumor which was marked by the decrease of the tumor volume and proliferation activity (p=0,001). The Kruskal Wallis result showed that there was no significant difference (p<0,33) in the tumor weight. Spearman correlation study significantly (p=0,03) indicated that there was a positive correlation between the cell proliferation activity and the growth of the tumor but in a weak correlation (r=0,39). Therefore, it could be concluded that the methanol extract of soursop leaf (Annona muricata Linn) can inhibit the growth rate of tumor volume as well as the proliferation activity of the breast cancer cell of C3H mice and it worked optimally at 30 mg/kg BB dose.;Breast cancer is a multifactor disease that has been a leading cause of woman’s mortality. Treatments for breast cancer such as surgery, radiotherapy, and chemotherapy have their own side effects, so that alternative treatments such as herbal medicine are needed. Soursop leaf (Annona muricata Linn) has been reported to have antitumor and cytotoxic effects, but only few conducted in vivo, an advanced research is needed to find the effectiveness and the inhibition pathway of the soursop leaf. The purpose of this research is to find out the inhibition capacity and the effective dose of soursop leaf methanol extract (Annona muricata Linn) against the development of C3H mice’s breast cancer in vivo. There were thirty mice of C3H strain which were transplanted with breast tumor and they were divided into five groups consisting of negative control group which was given only solvent CMC 0.5%, a positive control group which was given doxorubicin, a dose group of 15 mg/kg BB, a dose group of 30 mg/kg BB, and a dose group of 45 mg/kg BB. Each mouse was given 0,2 cc soursop leaf extract every day for 21 days while the positive control group was given doxorubicin 0,03 μg/20 gram BB once a week for 21 days intravenously. The length and the width of the tumor were measured at the beginning and also measured once a week during the experiment process to gain the data of the tumor volume. At the end of the research, the tumor of the mice was lifted and weighed and it was stained by AgNOR to measure the proliferation activity of the cell. The Anova result showed that there was a significant difference (p=0,007) between treatment against the development of tumor which was marked by the decrease of the tumor volume and proliferation activity (p=0,001). The Kruskal Wallis result showed that there was no significant difference (p<0,33) in the tumor weight. Spearman correlation study significantly (p=0,03) indicated that there was a positive correlation between the cell proliferation activity and the growth of the tumor but in a weak correlation (r=0,39). Therefore, it could be concluded that the methanol extract of soursop leaf (Annona muricata Linn) can inhibit the growth rate of tumor volume as well as the proliferation activity of the breast cancer cell of C3H mice and it worked optimally at 30 mg/kg BB dose.;Breast cancer is a multifactor disease that has been a leading cause of woman’s mortality. Treatments for breast cancer such as surgery, radiotherapy, and chemotherapy have their own side effects, so that alternative treatments such as herbal medicine are needed. Soursop leaf (Annona muricata Linn) has been reported to have antitumor and cytotoxic effects, but only few conducted in vivo, an advanced research is needed to find the effectiveness and the inhibition pathway of the soursop leaf. The purpose of this research is to find out the inhibition capacity and the effective dose of soursop leaf methanol extract (Annona muricata Linn) against the development of C3H mice’s breast cancer in vivo. There were thirty mice of C3H strain which were transplanted with breast tumor and they were divided into five groups consisting of negative control group which was given only solvent CMC 0.5%, a positive control group which was given doxorubicin, a dose group of 15 mg/kg BB, a dose group of 30 mg/kg BB, and a dose group of 45 mg/kg BB. Each mouse was given 0,2 cc soursop leaf extract every day for 21 days while the positive control group was given doxorubicin 0,03 μg/20 gram BB once a week for 21 days intravenously. The length and the width of the tumor were measured at the beginning and also measured once a week during the experiment process to gain the data of the tumor volume. At the end of the research, the tumor of the mice was lifted and weighed and it was stained by AgNOR to measure the proliferation activity of the cell. The Anova result showed that there was a significant difference (p=0,007) between treatment against the development of tumor which was marked by the decrease of the tumor volume and proliferation activity (p=0,001). The Kruskal Wallis result showed that there was no significant difference (p<0,33) in the tumor weight. Spearman correlation study significantly (p=0,03) indicated that there was a positive correlation between the cell proliferation activity and the growth of the tumor but in a weak correlation (r=0,39). Therefore, it could be concluded that the methanol extract of soursop leaf (Annona muricata Linn) can inhibit the growth rate of tumor volume as well as the proliferation activity of the breast cancer cell of C3H mice and it worked optimally at 30 mg/kg BB dose., Breast cancer is a multifactor disease that has been a leading cause of woman’s mortality. Treatments for breast cancer such as surgery, radiotherapy, and chemotherapy have their own side effects, so that alternative treatments such as herbal medicine are needed. Soursop leaf (Annona muricata Linn) has been reported to have antitumor and cytotoxic effects, but only few conducted in vivo, an advanced research is needed to find the effectiveness and the inhibition pathway of the soursop leaf. The purpose of this research is to find out the inhibition capacity and the effective dose of soursop leaf methanol extract (Annona muricata Linn) against the development of C3H mice’s breast cancer in vivo. There were thirty mice of C3H strain which were transplanted with breast tumor and they were divided into five groups consisting of negative control group which was given only solvent CMC 0.5%, a positive control group which was given doxorubicin, a dose group of 15 mg/kg BB, a dose group of 30 mg/kg BB, and a dose group of 45 mg/kg BB. Each mouse was given 0,2 cc soursop leaf extract every day for 21 days while the positive control group was given doxorubicin 0,03 μg/20 gram BB once a week for 21 days intravenously. The length and the width of the tumor were measured at the beginning and also measured once a week during the experiment process to gain the data of the tumor volume. At the end of the research, the tumor of the mice was lifted and weighed and it was stained by AgNOR to measure the proliferation activity of the cell. The Anova result showed that there was a significant difference (p=0,007) between treatment against the development of tumor which was marked by the decrease of the tumor volume and proliferation activity (p=0,001). The Kruskal Wallis result showed that there was no significant difference (p<0,33) in the tumor weight. Spearman correlation study significantly (p=0,03) indicated that there was a positive correlation between the cell proliferation activity and the growth of the tumor but in a weak correlation (r=0,39). Therefore, it could be concluded that the methanol extract of soursop leaf (Annona muricata Linn) can inhibit the growth rate of tumor volume as well as the proliferation activity of the breast cancer cell of C3H mice and it worked optimally at 30 mg/kg BB dose.]"

"Terapi penyakit degeneratif menggunakan sel punca mesenkim (SPM) dikembangkan dengan pendekatan seluler ataupun dengan conditioned medium (CM) yang mengandung faktor pertumbuhan dan vesikel ekstraseluer (VE). Sel punca kanker merupakan populasi kecil sel dalam jaringan kanker yang berkaitan dengan resistensi terapi. Belum diketahui dampak VE SPM tali pusat terhadap kepuncaan sel kanker payudara. Penelitian ini bertujuan menganalisis dampak pemberian VE SPM tali pusat terhadap kepuncaan sel kanker payudara. VE diisolasi dengan kromatografi kolom; diidentifikasi dengan mikroskop konfokal dan transmission electron microscope. Internalisasi VE oleh sel kanker payudara dikonfirmasi dengan mikroskop konfokal. Analisis viabilitas sel pasca kokultur VE dilakukan menggunakan trypan blue exclusion assay, ekspresi mRNA OCT4 dengan qRT-PCR, ekspresi protein OCT4 dengan Western Blot, aktivitas enzim ALDH dengan ALDEFLUOR™. Hasil, VE SPM tali pusat berhasil diisolasi serta diidentifikasi. Derajat internaliasasi VE oleh ketiga jenis sel kanker payudara berbeda. VE 5% meningkatkan viabilitas ketiga jenis sel serta ekspresi mRNA OCT4 sel MCF7 dan ALDH+. Tingkat ekspresi protein OCT4 sel MCF7 dan ALDH+ berbanding terbalik dengan peningkatan konsentrasi VE. VE 5% meningkatkan ekspresi protein OCT4 sel MDA-MB-231. VE 5% meningkatkan aktivitas ALDH ketiga sel kanker payudara. Pada VE 10%, aktivitas ALDH sel MDA-MB-231 dan MCF7 menurun, namun pada sel ALDH+ meningkat. Kesimpulan, pemberian VE SPM tali pusat dengan konsentrasi yang berbeda memberikan dampak berbeda terhadap kepuncaan berbagai sel kanker payudara, berkaitan dengan regulasi ekspresi OCT4 dan aktivitas ALDH.

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Therapy of degenerative diseases using umbilical cord mesenchymal stem cells (UCMSCs) are currently developed either using the cell or the conditioned medium containing extracellular vesicles (EVs). Cancer stem cells are a minor subpopulation of cells within cancerous tissue that had been associated with therapy resistance. This study aimed to investigate the effect of EVs secreted by UCMSC (UCMSC-EVs) on the stemness of human breast cancer cells. UCMSC-EVs were isolated using SEC, then identified using confocal microscope and TEM. UCMSC-EV uptake by MDA-MB-231, MCF7, and ALDH+ cells was analyzed by confocal microscope. The viability of co-cultured breast cancer cells was determined using trypan blue exclusion assay, mRNA and protein expression of OCT4 as well as ALDH activity were analyzed qRT-PCR, Western Blot, and ALDEFLUOR™, respectively. As the result, UCMSC-EVs were successfully isolated and identified. The internalization ability of each type of breast cancer cell seemed different. Notably, 5% EVs increased the viability of those three cells. Five percent of EVs increased the mRNA expression of OCT4. On MCF7 and ALDH+ cells, the higher the EVs concentration given, the lower expression of OCT4 protein was. Supplementation of EVs 5% increased the ALDH activity of cells. In conclusion, supplementation of UCMSC-EVs in different concentrations gives different impacts in terms of stemness that was correlated with OCT4 and ALDH regulation within the treated cells."

"Latar Belakang : FGF2 merupakan ligan bagi Fibroblast Growth Factor Receptor2(FGFR2). Interaksi dengan reseptor ini memediasi dimerisasi reseptor, fosforilasi, dan aktivasi jalur pensinyalan, seperti jalur Ras-MAPK dan PI3K. Mutasi yang berlebihan melalui sumbu FGF / FGFR dapat menginduksi proliferasi sel kanker, memicu angiogenesis dan limfogenesis, yang mendorong terjadinya metastasis. Penelitian ini mencoba mengevaluasi peran FGF2 pada metastasis kelenjar getah bening aksila pada pasien kanker payudara stadium dini. Tujuan : Mengetahui hubungan nilai ekspresi FGF 2 pada tumor primer terhadap kejadian metastasis kelenjar getah bening aksila. Metode : Digunakan studi potong lintang dengan mengevaluasi ekspresi FGF2 pada 47 pasien kanker payudara stadium dini yang menjalani mastektomi di Rumah Sakit Umum Pusat Nasional Cipto Mangunkusumo (RSCM) pada periode Januari 2014 sampai Desember 2018. Ekspresi FGF2 diperiksa dengan pemeriksaan imunohistokimia, kemudian dievaluasi dan dihubungkan antara ekspresi FGF2 dengan metastasis kelenjar getah bening aksila. Hasil : Uji Chi Square memperlihatkan nilai p=0.044 (p<0.05) yang menunjukkan bahwa terdapat hubungan yang signifikan antara nilai FGF2 pada tumor payudara dengan kejadian metastasis kelenjar getah bening aksila. Odds ratio 4,22 (CI 95% 0,983-18,1). Kesimpulan : Peran FGF2 dalam metastasis kelenjar getah bening berhubungan dengan interaksi antara berbagai faktor limfangiogenik dalam mempromosikan limfangiogenesis dan metastasis limfatik. Ekspresi FGF2 yang tinggi memiliki korelasi signifikan dengan angka kejadian metastasis kelenjar getah bening aksila.

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Background : FGF2 is a ligand for Fibroblast Growth Factor Receptor 2 (FGFR2). Interaction with this receptor mediate dimerization of receptor, phosphorilation, and activation of signaling pathway, such as Ras-MAPK and PI3K. Overmutation through FGF/FGFR induced proliferation of cancer cells, promoted angiogenesis, lymphogenesis, and metastasis. This study tried to evaluate the role of FGF2 in axillary lymph node metastasis in early-stage breast cancer patients.

Aim : To determined the relationship of FGF 2 expression values in primary tumors to the incidence of axillary lymph node metastases.

Methods :A cross-sectional study was used by evaluating the expression of FGF2 in 47 early-stage breast cancer patients who underwent a mastectomy at the Cipto Mangunkusumo National Center General Hospital (RSCM) from January 2014 to Desember 2018. FGF2 expression was examined by immunohistochemistry, then evaluated and linked between expression FGF2 with axillary lymph node metastases.

Results : The Chi Square test had a value of p=0.044 (p<0.05) that showed there was a significant relationship between FGF2 value in breast tumors with the incidence of axillary lymph node metastasis. Odds ratio 4.22 (95% CI 0.983-18.1).

Conclusions The role of FGF2 in lymph node metastasis is related to the interaction between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis. High expression of FGF2 has a significant correlation with the incidence of axillary lymph node metastasis."

"Kanker payudara adalah jenis kanker yang memiliki kasus baru terbanyak dan penyebab kematian tertinggi di kalangan wanita. Hal tersebut menjadikan pemahaman mengenai konsep pengobatan presisi (precision medicine) perlu dikembangkan, salah satunya dengan penggunaan kultur primer dari jaringan kanker pasien. Epidermal growth factor receptor (EGFR) telah dilaporkan umum digunakan sebagai marker prognostik kanker payudara melalui deteksi protein menggunakan metode immunohistokimia (IHK). Namun, metode tersebut memiliki kekurangan dalam menjadi acuan penentuan terapi adjuvant. Penggunaan kultur primer sebagai pengganti cell lines dalam penelitian kanker perlu terus dikembangkan karena lebih mewakili karakteristik fenotipe dan genotipe dari jaringan kanker in vivo. Oleh sebab itu, penelitian ini bertujuan untuk mengetahui tingkat ekspresi relatif gen EGFR pada sampel kultur primer dan jaringan asalnya serta mengetahui perbandingan ekspresi relatif gen EGFR pada sampel jaringan jinak dan jaringan ganas kanker payudara. Metode yang digunakan, yaitu melalui deteksi mRNA gen EGFR dengan semi kuantitatif RT-PCR pada dua pasien yang mewakili jaringan jinak dan ganas. Hasil penelitian menunjukkan tidak terdapat perbedaan signifikan antara ekspresi EGFR pada kultur primer dan jaringan asal, serta ekspresi EGFR pada jaringan ganas lebih tinggi dibandingkan dengan jaringan jinak. Berdasarkan hasil yang diperoleh, dapat disimpulkan bahwa kultur primer dapat dijadikan model alternatif dalam penelitian kanker, serta EGFR dapat dijadikan marker potensial dalam menentukan tingkat agresivitas kanker payudara.

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Breast cancer is a type of cancer that has a highest rate of incidence as well as mortality among women. This makes the understanding of the concept of precision medicine need to be continuously developed, in wich one of the methods is through using primary cultures from patient's tissue. It has been reported that epidermal growth factor receptor (EGFR) is commonly used as a prognostic marker of breast cancer through protein detection using the Immunohistochemical (IHC) method. However, this method has shortcomings in being a reference for determining adjuvant therapy. The use of primary culture as a subtitute cell lines in cancer research needs to be developed due to its more representative of the phenotype and genotype characteristics of cancer tissue in vivo. Therefore, this study aims to determine the relative expression level of the EGFR gene in primary culture sample and its tissue origin as well as comparing the relative expression of the EGFR gene in samples of benign tissue and malignant tissue of breast cancer. The method used is the detection of EGFR gene mRNA with semi-quantitative RT-PCR in two patients representing benign and malignant tissues. The results showed that there was no significant difference between EGFR expression in primary culture and tissue of origin, and EGFR expression in malignant tissue was higher than in benign tissue. Hence, it can be concluded that primary culture can be used as an alternative model in cancer research, and EGFR can be used as a potential marker in determining aggressiveness level of breast cancer."

"Latar belakang: Kanker payudara (KP) termasuk penyebab umum kematian pada wanita di dunia. Salah satu tumor marker yang digunakan sebagai penanda proliferasi sel kanker payudara yakni Ki-67. Ki-67 merupakan protein yang mudah diekspresikan di inti sel selama siklus sel, ekspresi Ki-67 yang tinggi menandakan semakin banyak sel yang berproliferasi. Terapi KP yang dijalani sekarang masih banyak ditemukan efek samping sehingga dibutukan terapi adjuvant dalam pengobatan KP yakni kedelai, kedelai dipilih karena murah, mudah dijangkau serta diyakini mampu menurunkan angka kejadian KP. Riset ini dilakukan untuk mengetahui efek lunasin dalam menurunkan ekspresi Ki-67 pada kelenjar payudara tikus. Metode: : Tikus jenis Sprague dewlay (SD) berjumlah 25 ekor dibagi secara acak ke dalam 5 kelompok yakni kelompok normal, kelompok kontrol negatif atau hanya dinduksi DMBA saja, kelompok tamoksifen, kelompok lunasin + tamoksifen dan kelompok lunasin kuratif. Setiap sedian jaringan kanker payudara diberi pewarnaan immunohistokimia terhadap Ki-67 kemudian akan dilihat dibawah mikroskop cahaya dengan pembesaran 400x,perhitungan jumlah sel dilakukan pada 5 lapang pandang untuk menilai ekspresi Ki-67.Perhitungan jumlah sel dengan menggunakan aplikasi Image J dan IHC profiler Hasil: Lunasin mampu menurunkan ekspresi Ki-67. Terdapat perbedaan bermakna pada setiap kelompok uji jika dibandingkan dengan kontrol negatif (p=0,000). Akan tetapi tidak terdapat perbedaan bermakna antara kelompok tamoksifen dengan kelompok terapi lunasin+ tamoksifen (p=0,961). Kesimpulan: Pemberian lunasin, tamoksifen dan lunasin+tamoksifen mampu menurunkan ekspresi Ki-67 pada sel kanker payudara tikus SD yang diinduksi DMBA. Kata kunci: DMBA, kanker payudara, lunasin, kedelai, protein Ki-67, tamoksifen.

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Introduction: Background: Breast cancer (KP) is a common cause of death in women around the world. One of the tumor markers used as a marker for breast cancer cell proliferation is Ki-67. Ki-67 is a protein that is easily expressed in the cell nucleus during the cell cycle, high Ki-67 expression indicates more cells are proliferating. There are still many side effects of KP therapy currently being carried out, so adjuvant therapy is needed in the treatment of KP, namely soybeans, soybeans were chosen because they are cheap, easy to reach, and are believed to be able to reduce the incidence of KP. This research was conducted to determine the effect of lunasin in reducing the expression of Ki-67 in the breast glands of rats. Method: 25 Sprague dewlay (SD) rats were randomly divided into 5 groups namely the normal group, negative control group or DMBA-induced only, tamoxifen group, lunasin + tamoxifen group and curative lunasin group. Each breast cancer tissue preparation was given immunohistochemical staining of Ki-67 and then viewed under a light microscope with 400x magnification, cell counts were performed in 5 fields of view to assess Ki-67 expression. Cell counts were performed using Image J and IHC profiler applications. Result: Lunasin was able to reduce the expression of Ki-67. There was a significant difference in each test group when compared to the negative control (p=0.000). However, there was no significant difference between the tamoxifen group and the lunasin + tamoxifen therapy group (p=0.961). Conclusion: Administration of lunasin, tamoxifen and lunasin+tamoxifen was able to reduce Ki-67 expression in DMBA-induced SD rat breast cancer cells. Keywords: DMBA, breast cancer, lunasin, soybean, Ki-67 protein, tamoxifen"

"ABSTRAKLatar Belakang: Keberadaan sel punca kanker payudara diduga berkontribusi dalam timbulnya resistensi terapi. Beberapa mekanisme yang mempengaruhi respons terapi pada kanker yaitu aktifnya jalur sinyal embrionik, hambatan apoptosis dan tingginya perbaikan DNA serta adaptasi sel punca kanker terhadap hipoksia dan stres oksidatif.Tujuan: Menganalisis profil ekspresi gen kepuncaan pada kanker payudara setelah terapi neoajuvan hormonal dan kemoterapi dilihat hubungannya dengan jalur apoptosis p53, jalur stres oksidatif NFkB dan penanda hipoksia HIF- serta respons terapi.Metode: Penelitian ini menggunakan sampel jaringan kanker payudara stadium IIIB dan IV sebelum terapi neoajuvan 46 sampel pre dan setelah terapi neoajuvan 46 sampel post . Total RNA diekstraksi kemudian dilakukan pengukuran ekspresi dengan menggunakan teknik Next Generation Sequencing Truseq targeted RNA expression Illumina dengan menggunakan panel sel punca, p53 dan NFkB. Selain itu juga ekspresi HIF-1 dan HIF-2 diukur dengan menggunakan qRT-PCR.Hasil: Setelah terapi neoajuvan, profil ekspresi gen kanker payudara yang memiliki respons molekuler yang baik pada jalur kepuncaan adalah CCNE1, CDC42, CTNNB1, HDAC2, PSEN1, PSENEN, pada jalur apoptosis adalah BIRC5, CASP8, CASP9, CDK1 dan PCNA, pada jalur stres oksidatif adalah SOD2, STAT1 dan TBK1, serta pada jalur hipoksia yaitu HIF-1 dan HIF-2 . Profil ekspresi gen dengan respons molekuler yang buruk pada jalur kepuncaan adalah ALDH1A1, ALDH2, CCND2, CXCL12, FZD7, IGF1, sedangkan pada jalur apoptosis adalah ATM dan BID. Respons histopatologis Miller Payne berkorelasi positif bermakna dengan ekspresi gen jalur apoptosis dengan respons molekuler yang baik BIRC5, CASP8, CDK1 , namun berkorelasi negatif bermakna dengan ekspresi gen ALDH1A1. Survival pasien kanker payudara berkorelasi negatif bermakna dengan ekspresi ALDH1A1 dan SOD2.Kesimpulan: Ekspresi gen ALDH1A1 dan SOD2 merupakan faktor penting untuk prediksi prognosis terapi neoajuvan sistemik pada pasien kanker payudara stadium lanjut.

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ABSTRACTIntroduction: The presence of breast cancer stem cells is considered to contribute to therapeutic resistance. There are some mechanisms affected therapy response in the cancer, such as active embryonic signaling pathways, inhibition of apoptosis and high DNA repair, adaptation to hypoxia and oxidative stress.Aim: to analyse the stemness gene expression profile in breast cancer after neoadjuvant chemotherapy and hormonal therapy correlated with apoptotic p53 , oxidative stress NFkB and hypoxia HIF- signaling pathways and also therapeutic responses.Methods: This study used breast tissue samples IIIB and IV before neoadjuvant therapy 46 pre samples and after neoadjuvant therapy 46 post samples . Total RNA was measured the expression profile using Next Generation Sequencing Truseq targeted RNA expression Illumina with stem cell, p53 and NFkB panels. In addition, HIF-1 and HIF-2 expression were measured using qRT-PCR. Results: After neoadjuvant therapy, the expression profiles of breast cancer genes that have good molecular responses in stem cells pathway are CCNE1, CDC42, CTNNB1, HDAC2, PSEN1, PSENEN, in apoptotic pathway are BIRC5, CASP8, CASP9, CDK1 and PCNA, in oxidative stress pathway are SOD2, STAT1 and TBK1, as well as in the hypoxic pathway HIF-1 and HIF-2 . Expression profiles with poor molecular responses in stem cells pathway are ALDH1A1, ALDH2, CCND2, CXCL12, FZD7, IGF1, while in apoptotic pathway are ATM and BID. Histopathologic response Miller Payne was significantly positively correlated with apoptotic pathway gene expression with good molecular response BIRC5, CASP8, CDK1 , but negatively significant correlated with ALDH1A1 gene expression. Survival of breast cancer patients significantly negatively correlated with ALDH1A1 and SOD2 expression. Conclusion: ALDH1A1 and SOD2 gene expression is an important factor for predicting the prognosis of systemic neoajuvan therapy in patients with advanced breast cancer."

"Breast cancer stem cells (BCSCs) dengan petanda Aldehida dehidrogenase 1-positif (ALDH1+) merupakan populasi minor dari sel-sel tumor dengan kemampuan tumorigenik yang tinggi dan bertahan terhadap stres oksidatif. Manganese superoksida dismutase (MnSOD) merupakan pertahanan utama terhadap superoksida yang diekspresikan spesifik di mitokondria, yang merupakan salah satu sumber utama stres oksidatif di dalam sel.  Sejauh ini, belum diketahui peranan MnSOD terhadap ketahanan hidup dan kepuncaan BCSC. Transfeksi in vitro pada BCSC (ALDH1+) dilakukan dengan menggunakan siRNA MnSOD spesifik dalam kondisi kultur standar. Total RNA dan protein diekstraksi dengan menggunakan TriPure® Isolation Reagent dan RIPA® lysis buffer. Viabilitas sel diukur dengan menggunakan trypan exclusion assay. Ekspresi relatif mRNA MnSOD dan OCT4 dianalisis dengan menggunakan one-step qRT-PCR. Aktivitas MnSOD diukur dengan menggunakan uji inhibisi xantin oksidase (RanSOD® kit). Kadar superoksida sel diukur dengan menggunakan uji dihidroetidium dan tumorigenik diukur dengan menggunakan mammosphere-forming unit. Setelah diinkubasi selama 48 jam dengan menggunakan siRNA dengan menggunakan dosis 80 pmol. Ekspresi relatif mRNA MnSOD mengalami penekanan sejumlah 0,17-kali (p<0,01), penurunan aktivitas spesifik MnSOD sebesar 70,4 %, peningkatan kadar superoksida sel menjadi 1,13-kali, penurunan ekspresi OCT4 menjadi 1,08-kali (p<0,05) dan penurunan mamosphere forming unit efficiency menjadi 36,5 % (p<0,05) dibandingkan dengan kontrol negatif. Viabilitas BCSC (ALDH1+) menurun sebanyak 75 %(p<-0,05) dibandingkan kontrol negatif. Hasil penelitian ini menunjukkan bahwa penekanan ekspresi MnSOD dapat menjadi target yang menjanjikan untuk menurunkan kepuncaan dan tumorigenitas BCSC (ALDH1+).

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Aldehyde dehydrogenase 1-positive (ALDH1+) breast cancer stem cells (BCSCs) are a small population of tumor cells with high capacity of tumorigenicity and oxidative stress. Manganese superoxide dismutase (MnSOD) is specifically expressed in mitochondria as the primary defense against superoxides, which are one of the causes of oxidative stress in cells. The aim of this study was to determine the impact of suppressing MnSOD expression using small interfering RNA (siRNA) on the stemness, tumorigenicity, and viability of BCSCs. In vitro transfection of ALDH1+ BCSCs was performed using 33 and 66 µM specific MnSOD siRNA under standard culture conditions. Total RNA and protein were extracted from the transfected cells using TriPure® Isolation Reagent and RIPA® lysis buffer. Cell viability was measured using a trypan blue exclusion assay. The relative expression of MnSOD and OCT4 mRNAs was analyzed by one step qRT-PCR. MnSOD activity was determined by xanthine oxidase inhibition assay (RanSOD® kit). Cellular superoxides were measured using a dihydroethidium assay and tumorigenicity was observed with mammosphere-forming unit.  After siRNA incubation for 48 hours, MnSOD was suppressed by 0.176-fold (p<0.01), MnSOD enzyme specific activity was reduced 70.4%, cellular superoxide levels increased by 1.13-fold, OCT4 expression was suppressed by 1.98-fold (p<0.05), and mammosphere-forming unit decreased by 36.5% (p<0.05) compared with the corresponding negative controls. The viability of the ALDH1+ BCSCs was reduced 75% (p< 0.05). Our results suggest that suppression of MnSOD expression may be a promising target to reduce stemness and tumorigenicity of ALDH1+ BCSCs."