Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer

Abstract

Mutations in genes that constitute the phosphatidylinositol 3-kinase (PI3K) pathway occur in >70% of breast cancers. Clinical and experimental evidence suggest that PI3K pathway activation promotes resistance to some of the current breast cancer therapies. PI3K is a major signaling hub downstream of human epidermal growth factor receptor (HER)2 and other receptor tyrosine kinases. PI3K activates AKT, serum/glucocorticoid regulated kinase (SGK), phosphoinositide-dependent kinase 1 (PDK1), mammalian target of rapamycin (mTOR), and several other molecules involved in cell cycle progression and survival. In estrogen receptor (ER)+ breast cancer cells, PI3K activation promotes estrogen-dependent and -independent ER transcriptional activity, which, in turn, may contribute to anti-estrogen resistance. Activation of this pathway also confers resistance to HER2-targeted therapies. In experimental models of resistance to anti-estrogens and HER2 inhibitors, pharmacological inhibition of PI3K/AKT/mTOR has been shown to overcome drug resistance. Early clinical data suggest that combined inhibition of either HER2 or ER plus inhibition of the PI3K pathway might be an effective strategy for treatment of respective HER2+ and ER+ breast cancers resistant to standard therapies. Here, we review alterations in the PI3K pathway in breast cancer, their association with therapeutic resistance, and the state of clinical development of PI3K pathway inhibitors.

Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer

“…Tumours of this subtype are in general hormone responsive with low proliferation rate and associated with a relatively good prognosis. Alterations in the PI3K/AKT pathway, mainly PIK3CA mutations, have been shown most frequent in the luminal subtypes, suggesting a crosstalk between ER and PI3K/AKT [3]. Aberrant PI3K/AKT signalling has been connected to poor response to anti-oestrogen therapies in several studies [20,[42][43][44][45][46][47][48][49][50].…”

“…In malignant cells, this pathway is commonly overstimulated and genetic and epigenetic alterations of the PI3K/AKT pathway are suggested as one driving cause of tumour development and progression [1,2]. In breast cancer, common aberrations include mutations in the PIK3CA and AKT genes, overexpression or activation of several upstream growth factors and receptor tyrosine kinases as well as loss of function of negative regulators, e.g., the phosphatase and tensin homologue (PTEN) [2,3]. Enhanced activation of the PI3K/AKT pathway has been suggested as a useful prognostic and treatment predictive factor in breast cancer.…”

Insulin Receptor Substrate 2-mediated Phosphatidylinositol 3-kinase Signaling Selectively Inhibits Glycogen Synthase Kinase 3β to Regulate Aerobic Glycolysis

“…Similarly, in vitro, mammary tumor cells derived from PyMT:Irs-1 Ϫ/Ϫ tumors have enhanced PI3K/mTor signaling, and this increased activity is dependent upon Irs-2 (14). The PI3K signaling pathway is one of the most commonly mutated pathways in cancer, including breast cancer (23,24). PI3K itself is an oncogene, and activating mutations have been observed in many types of cancer (25).…”

A survey of immunohistochemical biomarkers for basal-like breast cancer against a gene expression profile gold standard

“…This class II phosphatase is one of the many players involved in the negative regulation of phosphatidylinositol signaling, a pathway of particular interest for targeted therapies in basal-like and triple-negative breast cancers. [144][145][146][147][148] Located on chromosome 4q31.21, the INPP4B locus is commonly deleted in basal-like breast cancers and cell lines. [92][93][94][149][150][151] Previous studies characterizing INPP4B as a tumor suppressor were primarily focused at the genetic level; however, Gewinner et al 93 recently demonstrated successful immunohistochemical analysis of INPP4B and correlation between loss of INPP4B expression and decreased overall breast cancer survival.…”