Plasma membrane expression of G protein-coupled estrogen receptor (GPER)/G protein-coupled receptor 30 (GPR30) is associated with worse outcome in metachronous contralateral breast cancer

BACKGROUND: G 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. METHODS: Total GPR30 expression (GPR30(TOT)) and plasma membrane-localized GPR30 expression (GPR30(PM)) were analyzed by immunohistochemistry in primary (BC1; n(BC1) = 559) and contralateral BC (BC2; n(BC2) = 595), and in lymph node metastases (LGL; n(LGL1) = 213; n(LGL2) = 196). Death from BC (BCD), including BC death or death after documented distant metastasis, was used as primary end-point. RESULTS: GPR30(PM) in BC2 and LGL2 were associated with increased risk of BCD (HR(BC2) = 1.7, p = 0.03; HR(LGL2) = 2.0; p = 0.02). In BC1 and BC2, GPR30(PM) associated with estrogen receptor (ER)-negativity (p(BC1)<0.0001; p(BC2)<0.0001) and progesterone receptor (PR)-negativity (p(BC1) = 0.0007; p(BC2)<0.0001). The highest GPR30(TOT) and GPR30(PM) were observed in triple-negative BC. GPR30(PM) associated with high Ki67 staining in BC1 (p<0.0001) and BC2 (p<0.0001). GPR30(TOT) in BC2 did not associate with tamoxifen treatment for BC1. However, BC2 that were diagnosed during tamoxifen treatment were more likely to express GPR30(PM) than BC2 diagnosed after treatment completion (p = 0.01). Furthermore, a trend was observed that patients with GPR30(PM) in an ER-positive BC2 had greater benefit from tamoxifen treatment. CONCLUSION: PM-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.