PMID:17505062

Citation	Ma, Y, Hu, C, Riegel, AT, Fan, S and Rosen, EM (2007) Growth factor signaling pathways modulate BRCA1 repression of estrogen receptor-alpha activity. Mol. Endocrinol. 21:1905-23
Abstract	The breast cancer susceptibility gene BRCA1 is mutated in about one half of all hereditary breast cancer cases, and its expression is frequently decreased in sporadic cancers. Previously, we demonstrated a functional interaction between the BRCA1 and estrogen receptor-alpha (ER-alpha) proteins that causes inhibition of ER-alpha signaling. Here, we examined the role of growth factor signaling pathways in modulating this interaction. We found that underexpression of BRCA1 caused ligand-independent activation of ER-alpha that was mediated through phosphatidylinositol-3 kinase (PI3K)/c-Akt signaling. BRCA1 underexpression also enhanced estrogen-inducible ER-alpha activity in a PI3K/Akt-dependent manner. Exogenous c-Akt conferred estrogen-independent ER-alpha activation and rescued the BRCA1 repression of estrogen-stimulated ER-alpha activity. BRCA1 knockdown stimulated c-Akt activity, in part, by inhibiting the activity of protein phosphatase 2A, an enzyme that dephosphorylates Akt. ERs with point mutations of several growth factor-targeted serine residues (S167A, S118A, and S118/167A) were resistant to repression by BRCA1, although the single point mutant receptors still associated with the BRCA1 protein. The enhanced ER-alpha activity attributable to BRCA1 knockdown was dependent, in part, on serine residues 167 and 118 of ER-alpha. BRCA1 knockdown caused an increase in ER-alpha phosphorylation on serine-167 (but not serine-118 or serine-104/106) that was dependent on PI3K/Akt signaling and was mimicked by pharmacologic inhibition of protein phosphatase 2A. These findings suggest that BRCA1 regulates Akt signaling and the PI3K/Akt pathway modulates the ability of BRCA1 to repress ER-alpha, in part through serine phosphorylation events in the activation function-1 domain of ER-alpha.
Links	PubMed Online version:10.1210/me.2006-0397
Keywords	BRCA1 Protein/metabolism; BRCA1 Protein/physiology; Cell Line, Tumor; Estrogen Receptor alpha/antagonists & inhibitors; Estrogen Receptor alpha/metabolism; Female; Humans; Intercellular Signaling Peptides and Proteins/physiology; Male; Phosphatidylinositol 3-Kinases/metabolism; Proto-Oncogene Proteins c-akt/metabolism; Signal Transduction/physiology
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:BRCA1		GO:0033147: negative regulation of intracellular estrogen receptor signaling pathway	ECO:0000315:		P		Figure 6 and 7 D. When BRCA1 is silenced in the presence of E2, there is an increase in the phosphorylation of ER-alpha receptor.	complete CACAO 9376
HUMAN:BRCA1	involved_in	GO:0033147: negative regulation of intracellular estrogen receptor signaling pathway	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete

References

See Help:References for how to manage references in GONUTS.