Abstract
IntroductionActivation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Phosphatase and tensin homolog (PTEN), a negative regulator of this pathway, is typically lost in ER-negative breast cancer. We set out to clarify the role of reduced PTEN levels in endocrine resistance, and to explore the combination of newly developed PI3K downstream kinase inhibitors to overcome this resistance.MethodsAltered cellular signaling, gene expression, and endocrine sensitivity were determined in inducible PTEN-knockdown ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell and/or xenograft models. Single or two-agent combinations of kinase inhibitors were examined to improve endocrine therapy.ResultsModerate PTEN reduction was sufficient to enhance PI3K signaling, generate a gene signature associated with the luminal B subtype of breast cancer, and cause endocrine resistance in vitro and in vivo. The mammalian target of rapamycin (mTOR), protein kinase B (AKT), or mitogen-activated protein kinase kinase (MEK) inhibitors, alone or in combination, improved endocrine therapy, but the efficacy varied by PTEN levels, type of endocrine therapy, and the specific inhibitor(s). A single-agent AKT inhibitor combined with fulvestrant conferred superior efficacy in overcoming resistance, inducing apoptosis and tumor regression.ConclusionsModerate reduction in PTEN, without complete loss, can activate the PI3K pathway to cause endocrine resistance in ER-positive breast cancer, which can be overcome by combining endocrine therapy with inhibitors of the PI3K pathway. Our data suggests that the ER degrader fulvestrant, to block both ligand-dependent and -independent ER signaling, combined with an AKT inhibitor is an effective strategy to test in patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0430-x) contains supplementary material, which is available to authorized users.
Highlights
Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome
Inducible Phosphatase and tensin homolog (PTEN)-KD enhances PI3K signaling, decreases ER levels and activity, and generates a gene expression profile associated with the luminal B subtype To model reduced PTEN in ER+ breast cancer in vitro, we established stable clones of several ER+ breast cancer cell lines transduced with a Dox-inducible PTEN shorthairpin RNA lentiviral system [12]
This study shows that moderate PTEN reduction enhances multiple PI3K downstream signals, resulting in a global change of gene expression profile toward the luminal B subtype and endocrine resistance
Summary
Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in estrogen receptor α (ER)-positive breast cancer is associated with reduced ER expression and activity, luminal B subtype, and poor outcome. Oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, are associated with the luminal A subtype, high ER, and better clinical outcome in ER+ breast cancer patients receiving endocrine therapy [5,6]. These mutations are associated with only weak activation of the PI3K pathway, probably due to subsequent negative-feedback regulation. Loss of phosphatase and tensin homolog (PTEN), a negative regulator of the PI3K pathway, activates downstream protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling and may contribute to endocrine therapy resistance [7,8,9]. As found in the previous studies mentioned above [5,6], frequency of PIK3CA mutations was shown to be higher in luminal A than in luminal B breast cancer [11]
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