Abstract
BackgroundG protein-coupled estrogen receptor (GPER), or G protein-coupled receptor 30 (GPR30), is reported to mediate non-genomic estrogen signaling. GPR30 associates with breast cancer (BC) outcome and may contribute to tamoxifen resistance. We investigated the expression and prognostic significance of GPR30 in metachronous contralateral breast cancer (CBC) as a model of tamoxifen resistance.MethodsTotal GPR30 expression (GPR30TOT) and plasma membrane-localized GPR30 expression (GPR30PM) were analyzed by immunohistochemistry in primary (BC1; nBC1 = 559) and contralateral BC (BC2; nBC2 = 595), and in lymph node metastases (LGL; nLGL1 = 213; nLGL2 = 196). Death from BC (BCD), including BC death or death after documented distant metastasis, was used as primary end-point.ResultsGPR30PM in BC2 and LGL2 were associated with increased risk of BCD (HRBC2 = 1.7, p = 0.03; HRLGL2 = 2.0; p = 0.02). In BC1 and BC2, GPR30PM associated with estrogen receptor (ER)-negativity (pBC1<0.0001; pBC2<0.0001) and progesterone receptor (PR)-negativity (pBC1 = 0.0007; pBC2<0.0001). The highest GPR30TOT and GPR30PM were observed in triple-negative BC. GPR30PM associated with high Ki67 staining in BC1 (p<0.0001) and BC2 (p<0.0001). GPR30TOT in BC2 did not associate with tamoxifen treatment for BC1. However, BC2 that were diagnosed during tamoxifen treatment were more likely to express GPR30PM than BC2 diagnosed after treatment completion (p = 0.01). Furthermore, a trend was observed that patients with GPR30PM in an ER-positive BC2 had greater benefit from tamoxifen treatment.ConclusionPM-localized GPR30 staining is associated with increased risk of BC death when expressed in BC2 and LGL2. Additionally, PM-localized GPR30 correlates with prognostic markers of worse outcome, such as high Ki67 and a triple-negative subtype. Therefore, PM-localized GPR30 may be an interesting new target for therapeutic exploitation. We found no clear evidence that total GPR30 expression is affected by tamoxifen exposure during development of metachronous CBC, or that GPR30 contributes to tamoxifen resistance.
Highlights
Metachronous contralateral breast cancer (CBC) is a second, presumably independent primary tumor (BC2) developed in the contralateral breast after the first breast cancer (BC1)
In the first primary BC (BC1) and the second primary BC (BC2), GPR30PM associated with estrogen receptor (ER)-negativity and progesterone receptor (PR)-negativity
G protein-coupled estrogen receptor in metachronous contralateral breast cancer och Brostcancer; Skåne County Council’s Research and Development Foundation; Swedish Governmental Funding of Clinical Research within the National Health Service The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Summary
Metachronous contralateral breast cancer (CBC) is a second, presumably independent primary tumor (BC2) developed in the contralateral breast after the first breast cancer (BC1). Efforts aimed to further understand resistance mechanisms have led to a number of important discoveries, including pathological epigenetic changes or mutations in the ESR1 gene, and interference with other growth stimulatory signaling pathways. These mechanisms subsequently result in augmented receptor activity, ligand-independent growth and transcription, or reduced drug sensitivity [6, 9, 10]. Despite these discoveries, ER remains the only predictive marker for endocrine treatment. We investigated the expression and prognostic significance of GPR30 in metachronous contralateral breast cancer (CBC) as a model of tamoxifen resistance.
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