Abstract 3770: ER-α36-mediated non-genomic estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells .

Abstract

Abstract Accumulating experimental and clinical evidence indicated that breast cancer may arise from mammary stem/progenitor cells that posses the features like the ability of self-renewal and tumor generation from very few cells, slow cell division, differentiation into different lineages, selective resistance to radio- and chemo-therapy, constitutive activation of anti-apoptotic pathways and induction of angiogenesis, the ability to migrate and spread in metastasis. Many signaling pathways involved in regulation of normal mammary stem cells including Hedgehog, Bmi-1, Wnt, NOTCH, HER-2, p53 and PTEN/Akt/β-catenin pathways have been identified to play roles in breast cancer stem/progenitor cells. However, the involvement of estrogen signaling, a major signaling pathway in breast cancer development, in regulation of breast cancer stem/progenitor cells has not been well established, mainly because expression of estrogen receptor-α (ER-α) in breast cancer stem/progenitor cells remains controversial. Previously, we have identified and cloned a novel variant of ER-α, ER-α36, that is mainly expressed near the plasma membrane and in the cytoplasm, and mediates non-genomic estrogen signaling such as activation of the MAPK/ERK and PI3K/AKT signaling pathways. In this study, we ivestigated the function of ER-α36 in regulation of breast cancer stem/progenitor cells. We found that ER-α36 was highly expressed on the plasma membrane of the breast cancer stem/progenitor cells while the original ER-α was expressed outside of the cell nuclei. We also found that the genomic estrogen signaling was down-regulated in ER-positive breast cancer stem/progenitor cells. ER-positive breast cancer cells with forced expression of recombinant ER-α36 exhibited increased populations of stem/progenitor cells and high tumor seeding efficiency. Estrogen treatment significantly increased the population of breast cancer stem/progenitor cells while failed to do so in ER-positive breast cancer cells with knocked-down expression levels of ER-α36. We further found that estrogen positively regulates breast cancer stem/progenitor cells through ER-α36-mediated non-genomic estrogen signaling pathways such as activation of the PI3K/AKT pathway. Thus, our results demonstrated that the novel variant of ER-α, ER-α36 plays an important role in estrogen regulation of ER-positive breast cancer stem/progenitor cells. Citation Format: Hao Deng, Xintian Zhang, Molin Wang, Mingxi Guo, Lijiang Liu, Zhaoyi Wang. ER-α36-mediated non-genomic estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3770. doi:10.1158/1538-7445.AM2013-3770