Figure 4.
IL-8 participates in the HRG-driven endocrine resistance program in ER+ breast cancer cells. The regulatory actions of IL-8 on ER signaling can be related to the HER2:HER3-regulated stage of endocrine responsiveness. In the absence of persistent HER2:HER3 signaling, IL-8 expression might be part of a negative-feedback regulatory mechanism to fine-tune ER signaling. Accordingly, blockade of such negative feedback leads to exacerbated ERα transcriptional activation in response to E2. Autocrine HRG-induced heterodimerization and activation of HER2/HER3 stimulate the up-regulation of IL-8 expression and secretion, which in turn might further potentiate the non-genomic (e.g., MAPK- and PI3K-driven) unliganded transcriptional activity of ER characteristic of the endocrine-resistant phenotype in ER+ breast cancer cells.