Abstract 2884: PELP-1 promotes adverse endocrine therapy response in ER+ breast cancer

Abstract

Abstract Introduction: Despite the benefits of endocrine therapy for the management of ER positive breast cancer, not all patients respond equally leading to resistance and associated disease relapse and progression. We previously reported that endocrine agents themselves may induce an invasive phenotype in ER positive breast cancers with low/aberrant expression of E-cadherin. Here we investigate this phenomenon further, and provide data supporting a role for the ER co-receptor PELP-1, in mediating an adverse response to endocrine agents. Methods: The effects of tamoxifen (‘tam'), fulvestrant (‘fas') and estrogen withdrawal (as a model for aromatase inhibitor therapy) on the invasive and migratory capacity of endocrine-sensitive MCF-7 and T47D cells, in the presence or absence of functional E-cadherin and/or PELP-1 (using siRNA knockdown), was assessed via matrigel invasion and Boyden chamber migration assays. The effects of endocrine therapies alongside E-cadherin/PELP-1 modulation on cell proliferation were also assessed by growth assays, and western blotting using phospho-specific antibodies was performed to investigate signalling pathway changes associated with endocrine-induced changes in invasion and migration. Results: Both tamoxifen and fulvestrant induced a pro-invasive and pro-migratory phenotype in ER positive breast cancer cells displaying a high basal expression of PELP-1 which was augmented in the context of poor cell-cell contact (mean fold increase in invasion with endocrine treatment was 3.1±1.2; p=0.002 [MCF7+tam] and 2.7±1.4; p=0.002 [MCF7+fas]. Mean fold increase in invasion with endocrine treatment + E-cadherin siRNA was 22.4±5., p<0.001 [MCF7+tam] and 18.6±2.2 [MCF7+fas]). This process occurred in a Src-dependent manner with Src inhibition reversing endocrine induced invasion/migration (mean fold increase in invasion with endocrine treatment + E-cadherin siRNA in the absence of Src activity was 1.3±0.5, p<0.001 [MCF7+tam] and 0.8±0.5; p<0.001 [MCF7+fas]). siRNA-mediated suppression of PELP1 also reduced endocrine treatment-induced invasion and migration to a similar extent as Src suppression. In contrast to tam and fas, estrogen withdrawal did not induce an invasive or migratory phenotype irrespective ot E-cadherin or PELP1 expression level. Conclusion: Our data demonstrates that anti-estrogens exert pro-invasive effects on ER-positive breast cancer cell models, particularly in the absence of homotypic cell-cell contact through a mechanism involving PELP1 and Src. These results suggest that E-cadherin and PELP-1 may be potential biomarkers when deciding upon optimum adjuvant endocrine therapy, whereby tumors with high PELP-1 / low E-cadherin expression may benefit from estrogen withdrawal therapy via aromatase inhibition, instead of direct ER modulation/antagonism. Citation Format: Michael Rees, Chris Smith, Peter Barrett-Lee, Stephen Hiscox. PELP-1 promotes adverse endocrine therapy response in ER+ 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 2884.