Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor–positive human breast cancer

Abstract

Many breast cancers exhibit a degree of dependence on estrogen for tumor growth. Although several therapies have been developed to treat individuals with estrogen-dependent breast cancers, some tumors show de novo or acquired resistance, rendering them particularly elusive to current therapeutic strategies. Understanding the mechanisms by which these cancers develop resistance would enable the development of new and effective therapeutics. In order to determine mechanisms of escape from hormone dependence in estrogen receptor-positive (ER-positive) breast cancer, we established 4 human breast cancer cell lines after long-term estrogen deprivation (LTED). LTED cells showed variable changes in ER levels and sensitivity to 17β-estradiol. Proteomic profiling of LTED cells revealed increased phosphorylation of the mammalian target of rapamycin (mTOR) substrates p70S6 kinase and p85S6 kinase as well as the PI3K substrate AKT. Inhibition of PI3K and mTOR induced LTED cell apoptosis and prevented the emergence of hormone-independent cells. Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients. Our data suggest that upon adaptation to hormone deprivation, breast cancer cells rely heavily on PI3K signaling. Our findings also imply that acquired resistance to endocrine therapy in breast cancer may be abrogated by combination therapies targeting both ER and PI3K pathways.Introduction Two-thirds of breast cancers express estrogen receptor α (ER) and/ or progesterone receptor, which typically indicate a degree of estrogen dependence for growth. Treatment options for such patients include endocrine therapies that inhibit ER signaling, either by antagonizing ligand binding to ER (tamoxifen), downregulating ER (fulvestrant), or blocking estrogen biosynthesis (aromatase inhibitors [AIs]). Although endocrine therapies have changed the natural history of hormone-dependent breast cancer, many tumors exhibit de novo or acquired resistance (1). The only mechanism of resistance to endocrine therapy for which clinical data exist is overexpression of the HER2 protooncogene (also known as ErbB2; refs. 2-4). Because less than 10% of hormone receptor-positive breast cancers express high HER2 levels (2), mechanisms of endocrine resistance remain to be discovered for the majority of ER-positive breast cancers.Models of AI-resistant breast cancer have been based primarily on MCF-7 human breast cancer cells (5-7). To mimic the low estrogen levels seen in AI-treated patients (8) and gain a broad perspective of mechanisms of acquired hormone-independent growth common across several model systems, we generated long-term estrogen-deprived (LTED) derivatives from a panel of 4 ER-positive

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

“…AKT is a key node in the signaling network, with multiple substrates that mediate processes as diverse as cell proliferation, resistance to apoptosis, and glucose and fatty acid metabolism, which are activated in a wide range of solid and hematologic malignancies (10,11). AKT activation, either directly or indirectly by loss of PTEN and other means, has been shown to mediate resistance to inhibitors of receptor tyrosine kinases such as HER2 (12,13), antihormonal agents in breast (14)(15)(16) and prostate (17)(18)(19) cancers, and chemotherapy (20)(21)(22). Therefore, it is one of the most promising targets for cancer therapy, with a considerable platform of preclinical validation.…”

PI3K-based molecular signatures link high PI3K pathway activity with low ER levels in ER+breast cancer

“…The authors generated two molecular signatures, one proteomics-and another transcriptomics-based, and two different scoring systems, one for each signature. The PI3K proteomic signature, which was intended to reflect the status of PI3K pathway activation, was defined using previous background biological information of the pathway [3]. The signature is based on the measurement of the proteomic signal of seven well known key nodes in the pathway (Akt, mTOR, GSK3, S6K, S6 and PTEN).…”

“…For instance, there are clinical data suggesting that endocrine resistance of a subset of ER + tumors is mediated by HER2 overexpression [2]. The PI3K pathway has also been suggested to play a role in endocrine resistance, since PI3K is necessary for ER + breast cancer cells to adapt to hormone deprivation [3].…”

FOXO factors and breast cancer: outfoxing endocrine resistance

“…In addition to HER2, tyrosine receptor kinases implicated in the development of endocrine resistance include: epidermal growth factor receptor (EGFR), insulin-like growth factor receptor 1 (IGF1R), insulin receptor, receptor originated from nantes, and fibroblast growth factor receptor 1 (Frogne et al 2009, McClaine et al 2010, Turner et al 2010. All of these receptors converge on the PI3K-AKT signaling pathway, hyper-activation of which promotes the acquired estrogen-independent growth of ERC breast cancer cells (Miller et al 2010). They also activate the rat sarcoma viral oncogene homolog (RAS)/ERK signaling pathway, contributing to estrogen-independent ER activation; even in cultured breast cancer cells that are grown in the presence of tamoxifen.…”