GPR30: A potential therapeutic target in Triple‐negative Inflammatory Breast Cancer

Abstract

Inflammatory Breast Cancer (IBC) is rare and the most aggressive subtype of all breast cancers, with reported rapid progression, poor prognosis, and a unique clinical diagnosis (blockage of lymph vessels by tumor emboli). Approximately, 40% of IBC cases are classified as triple‐negative breast cancer (TNBC), meaning they test negative for hormone receptors (estrogen and progesterone) and the amplification of the epidermal growth factor receptor 2 (HER2), which result in no effective targeted therapies to date. However, 17β‐estrogen (E2) has been found to induce a non‐genomic cellular response to enhance oncogenic phenotypes in TN‐IBC and this has been associated with the presence of alternative estrogen receptors, including a novel G‐protein coupled estrogen receptor (GPR30). Recent studies have also reported a crosstalk between GPR30 and the epidermal growth factor receptor (EGFR) signaling pathway in the presence of E2, which enhances the phosphorylation of the extracellular signal‐regulated kinase (ERK1/2) and protein kinase B (AKT), and promotes migration and invasion phenotypes in TN‐BC cells. However, the exact role of GPR30 in the non‐genomic signaling pathway in TN‐IBC remains elusive. We hypothesize that GPR30 is necessary to undergo the estrogen non‐genomic signaling pathway to induce ERK1/2 and AKT phosphorilation levels and enhance migration and proliferation activities in TN‐IBC cells after treatment with E2.MethodsWe measured phosphorylation levels of ERK1/2 and AKT kinases (by western‐blot), migratory activity (by wound‐healing assay), and tumor emboli formation (by 3D‐cell proliferation assay) after treatments in time‐points with E2 alone and in combination with G15, GPR30 antagonist drug, in TN‐IBC cells SUM149PT.ResultsThe combined G15 + E2 treatment significantly reduced E2‐induced ERK1/2 and AKT phosphorylation levels, as well as decreased migratory activity in SUM149PT cells, suggesting that GPR30 is necessary to undergo the estrogen non‐genomic signaling pathway and can regulate the ERK1/2 and AKT signaling cascade in TN‐IBC. Data acquired from these experiments will contribute to a better understanding of TN‐IBC’s molecular structure and create new opportunities to develop novel targeted therapies.