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Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer

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Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer

dc.contributor.author	Creighton, Chad J	es_ES
dc.contributor.author	Fu, Xiaoyong	es_ES
dc.contributor.author	Hennessy, Bryan T	es_ES
dc.contributor.author	Casa, Angelo J	es_ES
dc.contributor.author	Zhang, Yiqun	es_ES
dc.contributor.author	González-Angulo, Ana María	es_ES
dc.contributor.author	Lluch Hernández, Ana	es_ES
dc.contributor.author	Gray, Joe W	es_ES
dc.contributor.author	Brown, Powell H	es_ES
dc.contributor.author	Hilsenbeck, Susan G	es_ES
dc.contributor.author	Osborne, C Kent	es_ES
dc.contributor.author	Mills, Gordon B.	es_ES
dc.contributor.author	Lee, Adrian V	es_ES
dc.contributor.author	Schiff, Rachel	es_ES
dc.date.accessioned	2015-06-29T10:34:11Z
dc.date.available	2015-06-29T10:34:11Z
dc.date.issued	2010	es_ES
dc.identifier.citation	Breast Cancer Research : BCR Vol. 12 Issue 3: pp. R40-R40	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/44812
dc.description.abstract	IntroductionAccumulating evidence suggests that both levels and activity of the estrogen receptor (ER) and the progesterone receptor (PR) are dramatically influenced by growth-factor receptor (GFR) signaling pathways, and that this crosstalk is a major determinant of both breast cancer progression and response to therapy. The phosphatidylinositol 3-kinase (PI3K) pathway, a key mediator of GFR signaling, is one of the most altered pathways in breast cancer. We thus examined whether deregulated PI3K signaling in luminal ER+ breast tumors is associated with ER level and activity and intrinsic molecular subtype.MethodsWe defined two independent molecular signatures of the PI3K pathway: a proteomic (reverse-phase proteomic array) PI3K signature, based on protein measurement for PI3K signaling intermediates, and a PI3K transcriptional (mRNA) signature based on the set of genes either induced or repressed by PI3K inhibitors. By using these signatures, we scored each ER+ breast tumor represented in multiple independent expression-profiling datasets (four mRNA, n = 915; one protein, n = 429) for activation of the PI3K pathway. Effects of PI3K inhibitor BEZ-235 on ER expression and activity levels and cell growth were tested by quantitative real-time PCR and cell proliferation assays.ResultsWithin ER+ tumors, ER levels were negatively correlated with the PI3K activation scores, both at the proteomic and transcriptional levels, in all datasets examined. PI3K signature scores were also higher in ER+ tumors and cell lines of the more aggressive luminal B molecular subtype versus those of the less aggressive luminal A subtype. Notably, BEZ-235 treatment in four different ER+ cell lines increased expression of ER and ER target genes including PR, and treatment with IGF-I (which signals via PI3K) decreased expression of ER and target genes, thus further establishing an inverse functional relation between ER and PI3K. BEZ-235 had an additional effect on tamoxifen in inhibiting the growth of a number of ER+ cell lines.ConclusionsOur data suggest that luminal B tumors have hyperactive GFR/PI3K signaling associated with lower ER levels, which has been correlated with resistance to endocrine therapy. Targeting PI3K in these tumors might reverse loss of ER expression and signaling and restore hormonal sensitivity.	es_ES
dc.title	Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer	es_ES
dc.type	journal article	es_ES
dc.identifier.doi	10.1186/bcr2594	es_ES
dc.identifier.idgrec	070763	es_ES