The ‘dark side’ of tamoxifen: understanding adverse cellular response to endocrine therapy in ER+ breast cancer

Background: Endocrine resistance is a common problem in estrogen receptor positive (ER+) breast cancer, particularly in the advanced setting. Beyond the anticipated effects of endocrine resistance, recent evidence points towards some ER+ cancers exhibiting a counterintuitive, adverse response to endocrine treatments, particularly in the setting of E-cadherin deficiency. Here the effects of adverse cell response to endocrine therapy is explored, including responsible cellular mechanisms. The ER co-receptor PELP-1, found to be of importance in mediating a pro-invasive response to endocrine treatments, was further explored in relation to its function in ER+, as compared to triple negative breast cancer (TNBC). Methods: The effects of endocrine treatments on the proliferative and invasive/migratory capacity of ER+ and TNBC cells, in the presence or absence of functional E-cadherin and/or PELP-1, were determined using cell counting and trans-well Boyden chamber-based assays respectively. For TNBC cells, studies were extended into 3D culture models. Mechanistic studies on endocrine-mediated modulation of cell signalling were determined by Western blotting. Results: Tamoxifen and fulvestrant induced a pro-invasive/pro-migratory phenotype in ER+ MCF-7 cells that displayed a high basal expression of PELP-1. This effect was augmented in the setting of E-Cadherin suppression and regulated in a Src-dependent manner. In contrast, no adverse phenotype was observed with cells cultured in estrogen-deprived conditions. PELP-1 suppression reduced endocrine-induced invasion/migration in MCF-7 cells, whilst PELP-1 knockdown in TNBC cells inhibited endogenous invasion in 2D and 3D culture. Conclusion: ER-targeting anti-estrogens may be responsible for inducing an adverse cell phenotype in ER+ breast cancers that highly express PELP-1; this effect may be more apparent in tumours that are also E-cadherin deficient. Such tumours may benefit from treatment with aromatase inhibitors as opposed to ER-targeting agents. PELP-1 may be an important target for future therapy, and act as a biomarker, predicting response to treatment in ER+ and TNBC