Loss of ERα involved-HER2 induction mediated by the FOXO3a signaling pathway in fulvestrant-resistant breast cancer.

Patients with estrogen receptor alpha (ERα)-positive breast cancer are commonly treated with anti-estrogen drugs as an initial treatment strategy. Fulvestrant, an estrogen receptor antagonist, effectively blocks ERα signaling; however, long-term fulvestrant treatment induces drug resistance in the absence of ERα. In this study, we investigated the molecular mechanism underlying the loss of ERα, FOXO3a, and induction of HER2 in fulvestrant-resistant breast cancer. Short-term fulvestrant treatment degraded ERα proteins via the ubiquitin-proteasome degradation pathway in MCF7 cells. MCF7 cells turn into highly proliferative cells (fulvestrant-resistant cells: Ful-R) after long-term fulvestrant treatment. These cells exhibit markedly suppressed estrogen and progesterone receptor levels. The phosphorylation of EGFR, HER2, and ERK was induced in Ful-R, and these phosphorylation inhibitors suppressed cell proliferation in Ful-R. FOXO3a, a transcriptional regulator of ERα was decreased in Ful-R, and a ubiquitin-proteasome inhibitor restored the expression of FOXO3a. These results suggest that the suppression of FOXO3a and ERα led to the increased expression of TGF-α, EGFR, and HER2 and subsequent cell proliferation in Ful-R. This study highlights the potential development of therapeutic drugs targeting FOXO3a for the treatment of HER2-positive, estrogen, and progesterone receptor-negative her2-type proliferative breast cancers.