CSrc and Her2 Signaling Pathways Cooperate With Estrogen to Promote Estrogen Receptor Phosphorylation, Ubiquitination and Proteolysis in ER Negative Breast Cancers

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Abstract : Breast cancer is the most frequent cancer in women. On third of new breast cancers do not express estrogen receptor (ER) protein and these have a worse prognosis than ER positive breast cancers. The ER is a ligand activated transcription factor. Estrogen:ER binding stimulates rapid Src activation that feeds back to phosphorylate the ER and increases its transcriptional activity. Estrogen binding to the ER rapidly activates ubiquitin-dependent ER proteolysis which in turn regulates ER activity. The data that I present here suggest that Src activates ER proteolysis. Src inhibition impaired estrogen stimulated ER ubiquitylation and proteolysis. The weakly ER positive, MDA-MB-361 and ER negative, BT-20 breast cancer lines both have high Src activity. ER was increased by estrogen deprivation, proteasome inhibition. Src inhibitors impaired ER ubiquitylation and degradation both in vivo and in vitro. Src levels or activity were increased in primary ER negative breast cancers compared to ER positive. We proposed that Src, when recruited by ligand dependent or independent ER activation, leads to ER or co-activator phosphorylation to regulate ubiquitin-dependent ER degradation. Some ER negative breast cancers are estrogen responsive: they express ER mRNA but ER protein levels are undetectable due to accelerated Src mediated ER proteolysis. Oncogenic RTK and Src activation may alter phosphorylation of the ER or of key co-regulators to activate both ER proteolysis and ER target gene transcription. The elucidation of mechanisms underlying ER loss in ER negative breast cancer may indicate why these cancers are so clinically aggressive. Pathways identified may yield new targets for molecular based therapies for this treatment-resistant form of breast cancer.