Overcoming endocrine resistance due to reduced PTEN levels in estrogen receptor-positive breast cancer by co-targeting mammalian target of rapamycin, protein kinase B, or mitogen-activated protein kinase kinase

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.

FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer

“…In this study, we showed that FOXA1 overexpression in ER (4,5,8,37). We report here that increased levels of FOXA1 coordinate at least partly with ER in this transcriptional reprogramming, leading to perturbed gene signatures and signaling pathways associated with endocrine resistance.…”

“…Although there are many causes for resistance, the most predominant mechanisms include altered ER signaling and interactions between ER, its coregulators, and various growth factor pathways. These alterations facilitate adaptation from ligand-dependent to ligand-independent ER activation, which is further triggered by cross-talk with growth factor receptor (GFR) signaling pathways (3)(4)(5)(6). However, the key mediators of ER transcriptional reprogramming in promoting endocrineresistant (Endo-R) breast cancer remain poorly understood.…”

Challenges in the management of advanced, ER-positive, HER2-negative breast cancer

“…Upregulation of alternative signalling pathways is a third mechanism leading to endocrine resistance, and the role of the PI3K/AKT/mTOR pathway in this context has been heavily investigated. [32][33][34][35][36][37] Increased AKT activity was first recognized as a feature of aggressive cancer, and associated with endocrine resistance in breast cancer, where, in fact, AKT and PI3K can mediate growth signalling via ERα in the absence of oestrogen. 32,33 Activating mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, are common in breast cancer, being present in 45% of luminal A and 29% of luminal B tumours.…”

Identification of potential therapeutic targets by molecular profiling of 628 cases of uterine serous carcinoma

“…Hormone receptor status may also be used as biomarkers for targeted therapies. Recently, studies evaluating the prognosis of breast cancer patients suggest that PIK3CA mutations are significantly associated with ER/PR expression [23] and that PTEN, a negative regulator of this pathway, is typically lost in ER-negative breast cancer [24]. Herein we show molecular alteration that leads to enhanced PI3K pathway signaling in HR+ USC, and propose that inhibition of PI3K/AKT pathway may overcome endocrine resistance in the subset of HR negative patients.…”