Phytoestrogen Coumestrol as an Anticancer Therapy Against Triple‐Negative Inflammatory Breast Cancer

Abstract

Breast cancer is the second leading cause of death in females in the United States, being Inflammatory Breast Cancer (IBC) the most aggressive subtype. The 5‐year survival rate is 40% for IBC as compared to 85% survival rate in patients with other 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. Those cases, triple negative IBC (TN‐IBC), express an alternative isoform of estrogen receptor alpha, estrogen receptor alpha‐36, and GPR30. Importantly, several studies have shown that estrogen can activate non‐genomic signaling pathways involved in the acquisition of oncogenic phenotypes such as increased motility and invasion in triple negative (TNBC) and TN‐IBC. In fact, recent studies have shown that phytoestrogen like Cou, structurally similar to estradiol (E2), induces cell cycle arrest and apoptosis 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, TN‐IBC cells were treated with E2 or Cou and the effect on phosphorylation of downstream kinases (ERK and AKT) was analyzed by Western blot. Also, functional assays had been performed to determine the effect of treatment with E2 alone, Cou alone, and in combination on migration, proliferation and tumor emboli formation. Immunofluorescence in TN‐IBC 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 TN‐IBC and TNBC cell lines. Finally, treatment using previously reported IC50 (50μM) of Cou caused a decrease in cell viability in breast cancer cell lines. Also, in comparison to E2, Cou decrease migration, proliferation, and tumor emboli formation in TN‐IBC. In summary, TN‐IBC cells are responsive to E2 treatment making this signaling pathway attractive for the development of innovative therapeutic strategies. Importantly, these Cou preliminary studies show a potential anticancer activity in TN‐IBC cell lines.Support or Funding InformationUPR Fondos Institucionales para la Investigación (FIPI) and RISE program (5R25GM061151‐18)