Abstract
Abstract Around 15% of all breast cancers are classified as ER−/PR−/HER2−, or triple negative (TNBC). This subtype of breast cancer does not respond to traditional endocrine therapies or targeted agents against HER2 and is particularly invasive with a high rate of recurrence due to resistance of cancer stem cells against therapy. Currently no efficient treatments are available to target cancer stem cells in TNBC. With this unmet need, it is a necessity to determine the molecular mechanisms underlying stem cell biology in TNBC to develop better targeted therapies of this disease. Recent studies have shown that the subunits of the polycomb repressive complex 2 (PRC2), such as EZH2, have been linked to invasiveness, metastasis, and chemoresistance in TNBC. PRC2 consists of four core members: EZH2, SUZ12, EED and RbBP4/7 which together mediate H3K27 trimethylation to repress gene transcription. In addition to its role in gene regulation, PRC2 has been linked to the regulation of breast cancer stem cells. However, the function of RbBP4/7 in breast cancer and breast cancer stem cells is unknown. The purpose of this study is to examine the role of RbBP4/7 in PRC2 in maintenance of the H3K27me3 mark, regulation of cancer cell stemness, and breast tumorigenesis. Analyzing the expression of RbBP4/7 in publicly available data sets through ONCOMINE, we found that both RbBP4 and RbBP7 were overexpressed in breast cancers, especially TNBC, compared with normal breast tissues. Similar to EZH2, higher expression of RbBP4 and RbBP7 was correlated to higher incidence of metastasis and poor prognosis. Using RNA interference, we successfully knocked down RbBP4 and RbBP7 in TNBC cell lines SUM149 and MDA-MB-231. Our results show that knockdown of both RbBP4 and RbBP7 significantly decreases cell growth by 70%, reduces H3K27me3 levels and drastically inhibits the mammosphere forming capability of these breast cancer cell lines by 80%. In addition, there was an increase in apoptotic cells as assessed by Annexin V staining from 12% in untreated cells to 28% in the RbBP4/7 knockdown cells. Knockdown of either RbBP4 or RbBP7, on the other hand, only has a moderate effect on cell proliferation, H3K27me3 levels and mammosphere formation. Our studies indicate that together RbBP4 and RbBP7 help maintain PRC2 function and breast cancer stem cell phenotype and could be exploited as a novel therapeutic target for treating TNBC. The effects of RbBP4 and RbBP7 knockdown on target gene regulation and breast tumor initiation and progression using xenograft models are currently under investigation. Citation Format: Rebecca A. Reed, Miao-Chia Lo, Duxin Sun. Characterization of polycomb repressive complex 2 (PRC2) subunits retinoblastoma-binding protein 4 and 7 (RbBP4/7) in triple-negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 106. doi:10.1158/1538-7445.AM2015-106
Published Version
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