ErbB receptors can bind and phosphorylate insulin receptor substrates (IRS) and this may be critical for ErbB-mediated anti-estrogen resistance in breast cancer.
These results suggested WT1 promotes estrogen-independent growth and anti-estrogen resistance in ER-positive breast cancer cells presumably through activation of the signaling pathways mediated by the members of EGFR family.
These studies have also revealed a complex relationship with estrogen; while prolactin increases ERalpha expression, it does not require estrogenic ligand for lesion development, and indeed, in combination with the EGFR ligand, TGFalpha, prolactin can contribute to estrogen insensitivity.
Loss of ERalpha expression may be linked to the acquisition of anti-estrogen resistance and enhanced expression of the EGFR and of members of the S100 family of Ca2+-binding proteins may contribute to the outgrowth of resistant cells.