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Extranuclear ERα is associated with regression of T47D PKCα-overexpressing, tamoxifen-resistant breast cancer

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Title: Extranuclear ERα is associated with regression of T47D PKCα-overexpressing, tamoxifen-resistant breast cancer
Author(s): White, Bethany Perez; Molloy, Mary Ellen; Zhao, Huiping; Zhang, Yiyun; Tonetti, Debra A.
Subject(s): Breast cancer PKCα Extranuclear ERα
Abstract: Background: Prior to the introduction of tamoxifen, high dose estradiol was used to treat breast cancer patients with similar efficacy as tamoxifen, albeit with some undesirable side effects. There is renewed interest to utilize estradiol to treat endocrine resistant breast cancers, especially since findings from several preclinical models and clinical trials indicate that estradiol may be a rational second-line therapy in patients exhibiting resistance to tamoxifen and/or aromatase inhibitors. We and others reported that breast cancer patients bearing protein kinase C alpha (PKC alpha)-expressing tumors exhibit endocrine resistance and tumor aggressiveness. Our T47D:A18/PKC alpha preclinical model is tamoxifen-resistant, hormone-independent, yet is inhibited by 17 beta-estradiol (E2) in vivo. We previously reported that E2-induced T47D:A18/PKC alpha tumor regression requires extranuclear ER alpha and interaction with the extracellular matrix. Methods: T47D:A18/PKC alpha cells were grown in vitro using two-dimensional (2D) cell culture, three-dimensional (3D) Matrigel and in vivo by establishing xenografts in athymic mice. Immunofluoresence confocal microscopy and co-localization were applied to determine estrogen receptor alpha (ER alpha) subcellular localization. Co-immunoprecipitation and western blot were used to examine interaction of ER alpha with caveolin-1. Results: We report that although T47D:A18/PKC alpha cells are cross-resistant to raloxifene in cell culture and in Matrigel, raloxifene induces regression of tamoxifen-resistant tumors. ER alpha rapidly translocates to extranuclear sites during T47D: A18/PKC alpha tumor regression in response to both raloxifene and E2, whereas ER alpha is primarily localized in the nucleus in proliferating tumors. E2 treatment induced complete tumor regression whereas cessation of raloxifene treatment resulted in tumor regrowth accompanied by re-localization of ER alpha to the nucleus. T47D:A18/neo tumors that do not overexpress PKC alpha maintain ER alpha in the nucleus during tamoxifen-mediated regression. An association between ER alpha and caveolin-1 increases in tumors regressing in response to E2. Conclusions: Extranuclear ER alpha plays a role in the regression of PKC alpha-overexpressing tamoxifen-resistant tumors. These studies underline the unique role of extranuclear ER alpha in E2- and raloxifene-induced tumor regression that may have implications for treatment of endocrine-resistant PKC alpha-expressing tumors encountered in the clinic.
Issue Date: 2013-05
Publisher: BioMed Central
Citation Info: White, B. P., Molloy, M. E., Zhao, H. P., Zhang, Y. Y. and Tonetti, D. A. Extranuclear ER alpha is associated with regression of T47D PKC alpha-overexpressing, tamoxifen-resistant breast cancer. Molecular Cancer. 2013. 12. DOI: 10.1186/1476-4598-12-34
Type: Article
Description: © 2013 Perez White et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This is a copy of an article published in the Molecular Cancer © 2013 BioMed Central
URI: http://hdl.handle.net/10027/12820
ISSN: 1476-4598
Sponsor: NIH/NCI RO1 CA122914 (to DAT) and NIH/NIGMS T32 BM070388 (to BPW and MEM).
Date Available in INDIGO: 2014-03-18
 

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