标题：ER-alpha 36-Mediated Rapid Estrogen Signaling Positively Regulates ER-Positive Breast Cancer Stem/Progenitor Cells
作者：Deng, Hao; Zhang, Xin-Tian; Wang, Mo-Lin; Zheng, Hong-Yan; Liu, Li-Jiang; Wang, Zhao-Yi
作者机构：[Deng, Hao; Zhang, Xin-Tian; Wang, Mo-Lin; Wang, Zhao-Yi] Creighton Univ, Sch Med, Dept Med Microbiol, Omaha, NE 68178 USA.; [Deng, Hao; Zhang, Xin- 更多
通讯作者地址：[Wang, ZY]Creighton Univ, Sch Med, Dept Med Microbiol, Omaha, NE 68178 USA.
摘要：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 alpha, ER-alpha 36, with a molecular weight of 36 kDa. ER-alpha 36 lacks both transactivation domains AF-1 and AF-2 of the 66 kDa full-length ER-alpha (ER-alpha 66) 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-alpha 36-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-alpha 36 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-beta-estradiol (E2 beta) 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-alpha 36 expression. Cells with forced expression of recombinant ER-alpha 36, however, responded strongly to E2 beta treatment by increasing growth in vitro and tumor-seeding efficiency in vivo. The rapid estrogen signaling via the AKT/GSK3 beta pathway is involved in estrogen-stimulated growth of ER-positive breast cancer stem/progenitor cells. We concluded that ER-alpha 36-mediated rapid estrogen signaling plays an important role in regulation and maintenance of ER-positive breast cancer stem/progenitor cells.