Estrogen Non‐Genomic Signaling as a Potential Therapeutic Target in Inflammatory Breast Cancer

Abstract

Breast cancer is the second leading cause of death in females in the United States2, being Inflammatory Breast Cancer (IBC) one of the most aggressive subtypes. The poor prognosis for patients with IBC emphasizes the need to better understand the molecular signature of this disease with the goal of developing effective targeted therapeutics. To this date there is no effective targeted therapeutics, especially for those patients that account for approximately 20–40% of IBC cases with triple‐negative breast cancer (TNBC) classification3. Importantly, several studies have shown that estrogen can exert non‐genomic effects in IBC and non‐IBC TNBC, mediated by the expression of an alternate isoform of estrogen receptor alpha, estrogen receptor alpha‐36, and GPR305,7,9. In this context, estrogen can activate non‐genomic signaling pathways involved in the acquisition of oncogenic phenotypes such as increased motility and invasion in IBC cells. Phytoestrogens, like coumestrol (Cou), are natural compounds found in plants, specifically soybeans. Also, it is a polyphenolic compound that is structurally similar to estradiol (E2) and several studies have shown that coumestrol inhibits cell proliferation and migration in TNBC. We hypothesize (1) that estrogen non‐genomic signaling has an active role in the aggressive metastatic phenotype of IBC, and (2) that Cou has anticancer activity by inhibiting estrogen non‐genomic signaling in IBC. To test this hypothesis, these cells were treated with E2 and activation of downstream kinases (ERK and AKT) was analyzed by Western blot. Immunofluorescence in IBC SUM149 cell line and Western Blot of breast cancer cell lines showed expression of estrogen receptors. In addition, preliminary observations demonstrated that upon E2 treatment there was an activation of ERK and AKT kinase in both IBC and TNBC cell line. Finally, treatment using previously reported IC50 (50μM)10–12 of Cou caused a decrease in cell viability of breast cancer cell lines. In summary, IBC cells are responsive to E2 treatment making this signaling pathway attractive for the development of innovative therapeutic strategies. Importantly, these Cou preliminary studies shows a potential anticancer activity in IBC cell lines.Support or Funding InformationThis project is supported by UPR Fondos Institucionales para la Investigación (FIPI to E. Peterson ) and RISE program (5R25GM061151‐17 to I. Jiménez).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.