Abstract P5-06-07: A novel role for breast cancer associated protein 2 (BCA2) in regulation replication-stress mediated DNA damage responses

Abstract

Abstract Breast cancer associated gene 2 (BCA2) has been originally identified from invasive breast cancer cells and shown to be overexpressed in over 50% of invasive breast cancers. Its expression is known to be highly associated with estrogen receptor-alpha (ER-α) status and promote cell proliferation and invasive properties. Importantly, expression of BCA2 is minimal or undetectable in most normal cells and tissues, which makes it as a valuable biomarker for ER-α positive breast cancers and a potential therapeutic target. BCA2 protein is a RING and ZINC-finger domain containing E3 ubiquitin ligase that has been shown to auto-ubiquitylate and interact with several proteins including Rab7, tetherin, ubiquitin, Ubc9 and p21, which are involved in different cellular processes. However, most of these studies have been focused on tumor progression, migration and invasive properties and almost no information on its role in carcinogenesis. Since many RING and ZINC-finger domain containing ubiquitin ligases are implicated in oncogenic signaling and DNA damage responses (DDR), in this study we examined the role of BCA2 in regulation of spontaneous and chemotherapeutics induced DDR in different breast cancer cell lines (ER-α positive versus triple negative). Interestingly, siRNA mediated down regulation of BCA2 induced spontaneous DDR, such as activation of replication checkpoint, slow cell cycle progression and double strand breaks (γH2AX foci). Exposure of BCA2 knockdown cells to DNA topoisomerase inhibitors (camptothecin and etoposide) potentiated DDR induced by these drugs. However, the molecular basis for this enhanced DDR is yet to be determined. Consistent with the previous studies, BCA2 knockdown attenuated cell proliferation, and compromised migration and invasion properties of these cells. Moreover, this novel role for BCA2 in DDR strongly suggests its status may also influence tumor response to chemo and radiation therapies and in carcinogenesis process. Further evaluation of breast cancer cell’s responses to different chemotherapeutic agents revealed distinct cellular responses based on the status of BCA2 and ER-α status. Taken together, our studies implicate a novel role for BCA2 in regulation of DDR and its influence on tumor response to chemotherapy. Additionally, we aim to present E3 ligase dependent and independent roles of BCA2 in these processes and tumor responses to different therapeutic agents. Acknowledgment: This is work is supported by Abraham Mitchell Cancer Research Scholar Endowment grant. Citation Format: Yuan-Hao Lee, Kaushlendra Tripathi, David Clark, Komaraiah Palle. A novel role for breast cancer associated protein 2 (BCA2) in regulation replication-stress mediated DNA damage responses [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-06-07.