Exploring and Exploiting the Protein S100A7 as a New Target for Breast Cancer Therapy

摘要

S100A7 is strongly correlated with loss of estrogen receptor alpha (ER) expression in vivo. ER is absent in approximately 30% of breast cancers, is correlated with poor prognosis, and is a vital marker for response to endocrine therapy. Despite its importance, little is known about the mechanisms that drive the ER phenotype. Our previous work demonstrated that S100A7 expression can originate from inflammatory stress, and we hypothesized that this could also regulate ER. We have found that the inflammatory cytokine oncostatin-M (OSM) can potently suppress ER expression in MCF7 and T47D breast cancer cells in vitro, while this stimulus strongly enhances S100A7 expression. ER suppression originates at the mRNA level in a mechanism dependent on canonical MAP kinase signaling through the MEKK-ERK1/2 pathway. Loss of ER inhibits the ability of cells to proliferate and express key ER-target genes such as progesterone receptor in response to estrogen. In addition to ER suppression and S100A7 induction, OSM induces changes characteristic of the epithelial to mesenchymal transition (EMT), a process associated with metastasis in vivo. These include loss of E- cadherin and gain of key mesenchymal transcription factors such as snail and twist. Importantly, high expression of the oncostatin-M receptor (OSMR) in patient samples is strongly associated with poor prognosis and downregulation of ER activity, in accordance with our experimental observations.