(509.3) GPR30: A potential therapeutic target in Triple-negative Inflammatory Breast Cancer

Poster Board Number: A329

Xavier Bittman-Soto (University of Puerto Rico - Rio Piedras Campus), Adrian Rivera-Lopez (University of Puerto Rico - Rio Piedras Campus), Laura Mendez-Santacruz (University of Puerto Rico - Rio Piedras Campus), Esther Peterson-Peguero (University of Puerto Rico - Rio Piedras Campus)

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. 

Methods:   We 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. 

Results:  The 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.

RISE-UPRRP program Grant: 5R25GM061151-18
NIH Grant: 1R21CA253609-01