title: Enhanced SLC34A2 in breast cancer stem cell-like cells induces chemotherapeutic resistance to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling.
abstract: Even though early detection methods and treatment options are greatly improved, chemoresistance is still a tremendous challenge for breast cancer therapy. Breast cancer stem cells (BCSCs) represent a subpopulation that is central to chemoresistance. We aim to investigate the relationship between SLC34A2 and chemoresistance in BCSCs and identify the underlying mechanisms by which SLC34A2 regulates chemoresistance in BCSCs. Fluorescence Activated Cell Sorting (FACS) analysis showed the presence of a variable fraction of CD44(+)CD24(-) cells in 25 out of 25 breast cancer samples. We cultured primary breast cancer sample cells and breast cancer cell line cells to induce sphere formation in serum-free medium. Following sorting of CD44(+)CD24(-) cells from spheres, we showed that CD44(+)CD24(-) cells displayed stem cell-like features and were resistant to chemotherapy drug doxorubicin. Significantly, enhanced SLC34A2 expression correlated with chemoresponse and survival of breast cancer patients. We subsequently indicated that increased SLC34A2 expression in BCSCs directly contributed to their chemoresistance by a series of in vitro and in vivo experiments. Furthermore, we demonstrated that SLC34A2 induced chemoresistance in BCSCs via SLC34A2-Bmi1-ABCC5 signaling. Finally, we showed that ABCC5 was a direct transcriptional target of Bmi1 by chromatin immunoprecipitation (ChIP). In conclusion, our work indicated that decreased SLC34A2 expression sensitized BCSCs to doxorubicin via SLC34A2-Bmi1-ABCC5 signaling and shed new light on understanding the mechanism of chemoresistance in BCSCs. This study not only bridges the missing link between stem cell-related transcription factor (Bmi1) and ABC transporter (ABCC5) but also contributes to development of potential therapeutics against breast cancer.
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China.
authors.forename: Guanqun
authors.initials: G
authors.lastname: Ge
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China.
authors.forename: Can
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China.
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China.
authors.forename: Ligang
authors.initials: L
authors.lastname: Niu
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China.
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, NO. 277, Yantaxi Road, Xi'an, 710061, Shanxi Province, People's Republic of China. hejianjun_doc@yahoo.com.
authors.forename: Jianjun
authors.initials: J
authors.lastname: He
mesh_terms: D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008875:Middle Aged; D048054:Mitogen-Activated Protein Kinase 7 / Q000096:biosynthesis* / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D004317:Doxorubicin; D048054:Mitogen-Activated Protein Kinase 7; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb; C120809:ABCC5 protein, human; C493557:SLC34A2 protein, human; C481581:MAPK7 protein, human
keywords: ABCC5; Bmi1; Breast cancer stem cells; CD44+CD24−; Chemotherapeutic resistance; SLC34A2