Abstract 2179: Population remodeling in the acquisition of endocrine resistance in breast cancer

Abstract

Abstract The cell-cell interactions that occur within the breast tumor microenvironment are critical determinants of cancer cell fate. In the face of treatment, the theory of clonal evolution dominates current thinking. Thus, individual cells acquire a mutation(s) that provides a selection advantage where Darwinian selection acts at the single-cell level. We studied the effect of antiestrogen treatment on the population remodeling of admixtures of sensitive LCC1 (S) cells and resistant LCC9 (R) human breast cancer cells. R cells were derived from S cells by selection against antiestrogens. We labeled S cells with GFP and R cells with mCherry, mixed the cells in different ratios, and treated with antiestrogen or vehicle. Unlike other resistance phenotypes (e.g., MDR1-driven cytotoxic drug models), R cells do not outcompete S cells, nor do S cells restrain R cell growth. Rather, R cells protect S cells from treatment. Full communication of the resistance phenotype occurs at a 1:1 mixture of S:R; ~75% of the R phenotype transfer is evident at 10:1. These results reflect improved fitness conferred by population interactions, not clonal evolution. SILAC analysis of S and R cells (pure populations) implicate differential regulation of estrogen (E2) response-early; E2 response-late; glycolysis; fatty acid metabolism; mTORC1 signaling; peroxisome; unfolded protein response (UPR); oxidative phosphorylation in S vs. R cells. Clustering of iTRAQ-TAT data from pure and admixed S:R populations shows that the 1:1 and 5:1 treated, and the 1:1 untreated admixtures, cluster with pure R cells. Untreated 5:1 admixed cells cluster with untreated S cells. Thus, R and S cells alter each other's molecular signatures. Studies using scratch labeling and small-molecule inhibitors show that R cells communicate with S cells via both juxtacrine and paracrine interactions mediated by gap junctional intracellular communication and secreted microvesicles, respectively. The molecular features modified reflect our unifying hypothesis of signaling and cell function control in endocrine resistance. Citation Format: Rong Hu, Surojeet Sengupta, Catherine Sevigny, Zhen Zhang, Yue Wang, Robert Clarke. Population remodeling in the acquisition of endocrine resistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2179.