Abstract 1716: Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation

Abstract

Abstract Approximately 70% of newly diagnosed breast cancers express high levels of estrogen receptor alpha (ERα). However, de novo and acquired drug resistance to anti-estrogen agents limit the treatment of such patients, requiring the use of cytotoxic chemotherapy; many such patients have a poor prognosis. Therefore, resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen-receptor positive breast cancer. To address this challenge, a system biological approach by screening a library of siRNAs targeting an estrogen receptor- and aromatase-centered network, was used and identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells, and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent estrogen-receptor positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mTOR inhibitors in estrogen-independent cells but not estrogen-dependent cells. Phosphoproteomic profiles (results from reverse phase protein array, RPPA) under basal conditions and following TOB1 depletion identified significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. The translational significance of this new molecular mechanism of estrogen independence in human breast cancer will be fully determined when TOB1 inhibitors are developed to enable in vivo validation studies. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, which have potential translational significance for the management of patients with estrogen receptor-positive breast cancers. Citation Format: Yong-Wei Zhang, Rochelle E. Nasto, Rency Varghese, Sandra A. Jablonski, Ilya G. Serebriiskii, Rishi Surana, Valerie S. Calvert, Ionut Bebu, Joseph Murray, Lu Jin, Michael Johnson, Rebecca Riggins, Habtom Ressom, Emmanuel Petricoin III, Robert Clarke, Erica A. Golemis, Louis M. Weiner. Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation. [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 1716. doi:10.1158/1538-7445.AM2015-1716