title: ER-α36-mediated rapid estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells.
abstract: The breast cancer stem cells (BCSC) play important roles in breast cancer occurrence, recurrence and metastasis. However, the role of estrogen signaling, a signaling pathway important in development and progression of breast cancer, in regulation of BCSC has not been well established. Previously, we identified and cloned a variant of estrogen receptor α, ER-α36, with a molecular weight of 36 kDa. ER-α36 lacks both transactivation domains AF-1 and AF-2 of the 66 kDa full-length ER-α (ER-α66) and mediates rapid estrogen signaling to promote proliferation of breast cancer cells. In this study, we aim to investigate the function and the underlying mechanism of ER-α36-mediated rapid estrogen signaling in growth regulation of the ER-positive breast cancer stem/progenitor cells. ER-positive breast cancer cells MCF7 and T47D as well as the variants with different levels of ER-α36 expression were used. The effects of estrogen on BCSC's abilities of growth, self-renewal, differentiation and tumor-seeding were examined using tumorsphere formation, flow cytometry, indirect immunofluorence staining and in vivo xenograft assays. The underlying mechanisms were also studied with Western-blot analysis. We found that 17-β-estradiol (E2β) treatment increased the population of ER-positive breast cancer stem/progenitor cells while failed to do so in the cells with knocked-down levels of ER-α36 expression. Cells with forced expression of recombinant ER-α36, however, responded strongly to E2β treatment by increasing growth in vitro and tumor-seeding efficiency in vivo. The rapid estrogen signaling via the AKT/GSK3β pathway is involved in estrogen-stimulated growth of ER-positive breast cancer stem/progenitor cells. We concluded that ER-α36-mediated rapid estrogen signaling plays an important role in regulation and maintenance of ER-positive breast cancer stem/progenitor cells.
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, Nebraska, United States of America ; Jiangda Pathology Center, Jianghan University, Wuhan, Hubei, P. R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Deng
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, Nebraska, United States of America.
authors.forename: Xin-Tian
authors.initials: XT
authors.lastname: Zhang
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, Nebraska, United States of America ; Institute of Medical Genetics, School of Medicine, Shandong University, Jinan, Shandong, P. R. China.
authors.forename: Mo-Lin
authors.initials: ML
authors.lastname: Wang
authors.affiliation: Jiangda Pathology Center, Jianghan University, Wuhan, Hubei, P. R. China.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Zheng
authors.affiliation: Jiangda Pathology Center, Jianghan University, Wuhan, Hubei, P. R. China.
authors.forename: Li-Jiang
authors.initials: LJ
authors.lastname: Liu
authors.affiliation: Departments of Medical Microbiology and Immunology, Creighton University Medical School, Omaha, Nebraska, United States of America.
authors.forename: Zhao-Yi
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003001:Cloning, Molecular; D003094:Collagen / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D003094:Collagen