title: ER-α variant ER-α36 mediates antiestrogen resistance in ER-positive breast cancer stem/progenitor cells.
abstract: Accumulating evidence indicates that cancer stem cells (CSC) play important roles in breast cancer occurrence, recurrence and metastasis as well as resistance to therapy. However, the roles of breast cancer stem cells in antiestrogen resistance and the underlying molecular mechanisms have not been well established. Previously, we identified and cloned a novel variant of estrogen receptor α, ER-α36, with a molecular weight of 36kDa. ER-α36 mediates rapid antiestrogen signaling and is highly expressed in ER-positive breast cancer stem/progenitor cells. In this study, we investigated the function and the underlying mechanism of ER-α36-mediated antiestrogen signaling in ER-positive breast cancer stem/progenitor cells. ER-positive breast cancer cells MCF7 and T47D as well as variants with different levels of ER-α36 expression were used. The effects of antiestrogens tamoxifen and ICI 182, 780 on breast CSC's ability of growth, self-renewal, differentiation and tumor seeding were examined using tumorsphere formation, flow cytometry, indirect immunofluorences and in vivo xenograft assays. The underlying mechanisms were also analyzed with Western blot analysis. We found that the cancer stem/progenitor cells enriched from ER-positive breast cancer cells were more resistant to antiestrogens than the bulk cells. Antiestrogens increased the percentages of the stem/progenitor cells from ER-positive breast cancer cell through stimulation of luminal epithelial lineage specific ER-positive breast cancer progenitor cells while failed to do so in the cells with knocked-down levels of ER-α36 expression. Our results thus indicated that ER-α36-mediated antiestrogen signaling such as the PI3K/AKT plays an important role in antiestrogen resistance of ER-positive breast cancer stem/progenitor cells.
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, NE, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Deng
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, NE, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, NE, USA.
authors.forename: Xin-Tian
authors.initials: XT
authors.lastname: Zhang
authors.affiliation: Jiangda Pathology Center, Jianghan University, Wuhan, Hubei, PR China.
authors.forename: Li-Jiang
authors.initials: LJ
authors.lastname: Liu
authors.affiliation: Institute of Medical Genetics, School of Medicine, Shandong University, Jinan, Shandong, PR China.
authors.forename: Mo-Lin
authors.initials: ML
authors.lastname: Wang
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, NE, USA. Electronic address: zywang@creighton.edu.
authors.forename: Zhao-Yi
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D000077267:Fulvestrant; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol
keywords: Antiestrogen resistance; Cancer stem/progenitor cells; ER-positive breast cancer; ER-α36