Oestrogen Non-Genomic Signalling is Activated in Tamoxifen-Resistant Breast Cancer.

Coralie Poulard,Pascale A Cohen,Isabelle Treilleux,Julie Vendrell,Elisabetta Marangoni,Sandra E Ghayad,Julien Jacquemetton,Olivier Trédan,Muriel Le Romancer

doi:10.3390/ijms20112773

Abstract

Endocrine therapies targeting oestrogen signalling have significantly improved breast cancer management. However, their efficacy is limited by intrinsic and acquired resistance to treatment, which remains a major challenge for oestrogen receptor α (ERα)-positive tumours. Though many studies using in vitro models of endocrine resistance have identified putative actors of resistance, no consensus has been reached. We demonstrated previously that oestrogen non-genomic signalling, characterized by the formation of the ERα/Src/PI3K complex, is activated in aggressive breast cancers (BC). We wondered herein whether the activation of this pathway is also involved in resistance to endocrine therapies. We studied the interactions between ERα and Src or PI3K by proximity ligation assay (PLA) in in-vitro and in-vivo endocrine therapy-resistant breast cancer models. We reveal an increase in ERα/Src and ERα/PI3K interactions in patient-derived xenografts (PDXs) with acquired resistance to tamoxifen, as well as in tamoxifen-resistant MCF-7 cells compared to parental counterparts. Moreover, no interactions were observed in breast cancer cells resistant to other endocrine therapies. Finally, the use of a peptide inhibiting the ERα–Src interaction partially restored tamoxifen sensitivity in resistant cells, suggesting that such components could constitute promising targets to circumvent resistance to tamoxifen in BC.

Highlights

Breast cancer (BC) is the most common cancer among women worldwide [1]
Since the express the oestrogen receptor α (ERα)/Src/PI3K complex is highly expressed in aggressive ERα-positive breast cancers [20] and activation of the PI3K/Akt pathway is involved in resistance to endocrine therapies [26,27], we speculated that the activation of oestrogen non-genomic signalling was implicated in such resistance
In an attempt to understand the mechanism underlying the differences in these two resistant models, we analysed Src and PI3K expression in the different patient-derived xenografts (PDXs) models, and found that Src expression exclusively is increased in the HBCx22 TamR model compared to parental PDXs whereas no difference was observed in the HBC34 R model (Figure S1)

Summary

Introduction

Breast cancer (BC) is the most common cancer among women worldwide [1]. More than 75% of breast tumours express the oestrogen receptor α (ERα) in the nucleus and are commonly part of the group of luminal BCs. The main mechanisms underlying intrinsic resistance to tamoxifen are the lack of ERα expression and failure to convert tamoxifen into its active metabolite, while acquired resistance has been associated with a plethora of mechanisms. Those include alterations of ERα signalling, crosstalk between ERα and the growth factor network, activation of the PI3K–Akt–mTOR pathway, aberrant expression of cell-cycle regulators and induction of NFκB signalling [3,4]. ERα-positive tumours expressing high levels of ERα-36 appear to benefit less from tamoxifen treatment [8,9], probably because tamoxifen enhances stemness and promotes metastases via this receptor [10]. The G-protein coupled oestrogen receptor (GPER), an alternate oestrogen receptor with a different structure, has been associated with the development of tamoxifen resistance via a crosstalk with EGFR [11]

Methods

Results

Conclusion