PKA phosphorylation redirects ERα to promoters of a unique gene set to induce tamoxifen resistance

Abstract

Protein kinase A (PKA)-induced estrogen receptor alpha (ERa) phosphorylation at serine residue 305 (ERaS305-P) can induce tamoxifen (TAM) resistance in breast cancer. How this phospho-modification affects ERa specificity and translates into TAM resistance is unclear. Here, we show that S305-P modification of ERa reprograms the receptor, redirecting it to new transcriptional start sites, thus modulating the transcriptome. By altering the chromatin-binding pattern, Ser305 phosphorylation of ERa translates into a 26-gene expression classifier that identifies breast cancer patients with a poor disease outcome after TAM treatment. MYC-target genes and networks were significantly enriched in this gene classifier that includes a number of selective targets for ERaS305-P. The enhanced expression of MYC increased cell proliferation in the presence of TAM. We demonstrate that activation of the PKA signaling pathway alters the transcriptome by redirecting ERa to new transcriptional start sites, resulting in altered transcription and TAM resistance.

Minireview: Tipping the Balance: Ligand-Independent Activation of Steroid Receptors

“…Differences between ER␣ complexes induced by estrogen vs IGF-1 have also been reported for specific target sites (163). Both EGF and cAMP have been found to determine the ER␣ cistromes slightly differently from estrogen (83,164). To what extent this is affected by pioneer factors such as Forkhead box protein A1 (FoxA1) or partner transcription factors such as AP1 and NF-B or the differences in assembling transcription complexes needs further investigations.…”

“…Gene expression profiles controlled by ER␣ can substantially differ, depending on whether ER␣ is activated by estrogen, cAMP, EGF, or one of these in combination with OHT (83,164,165).…”

Complex Formation and Function of Estrogen Receptor α in Transcription Requires RIP140

“…Unfortunately, resistance to endocrine treatment is common. ERa can acquire additional agonistic features through altered kinase activities (24)(25)(26) or cofactor overexpression (27,28).…”

Harnessing protein kinase A activation to induce mesenchymal-epithelial programs to eliminate chemoresistant, tumor-initiating breast cancer cells

“…At present, the best defined contribution of PKA signaling to neoplastic transformation is found in endocrine-associated tumors, including those arising in the kidney, pituitary, thyroid, and testis, where elevated activation of PKA is highly associated with tumor aggression (32). Along these lines, PKA activation has also been linked to the induction of EMT programs due to its ability to promote cytoskeletal remodeling and migratory behaviors in malignant cells (33, 34); it also serves as a critical mediator of EMT programs activated by hypoxia (35), and as a potential driver of chemoresistance in breast cancer cells (36). Consistent with its dichotomous roles during tumorigenesis, PKA activation has also been linked to the induction of MET programs and a return to more differentiated phenotypes in certain cancers (37), an activity Pattabiraman and colleagues (25) attempted to exploit as a novel therapy in the treatment of metastatic breast cancers.…”