Overview of the relevance of PI3K pathway in HR-positive breast cancer

Abstract

One of the hallmarks of hormone receptor (HR)-positive breast cancer is its dependence on the phosphatidylinositol-3-kinase (PI3K) pathway. Here, we review the epidemiologic, functional, and pharmacologic interactions between oncogenic PI3K and the estrogen receptor (ER). We discuss the epidemiology of PI3K pathway alterations, mechanisms of resistance to PI3K inhibitors, and the current mechanistic landscape of crosstalk between PI3K and ER, which provide the rationale for dual ER and PI3K inhibition and is now a standard of care in the treatment of ER+ PIK3CA-mutant metastatic breast cancer. We outline newer studies in this field that delineate the clinically relevant overlaps between PI3K and parallel signaling pathways, insulin signaling, and ER epigenetic modifiers. We also identify several caveats with the current data and propose new strategies to overcome these bottlenecks.

Keywords: PIK3CA; AKT; PI3K inhibitors; PI3K pathway; breast cancer; estrogen receptor.

Figure 1.

Signaling by the phosphatidylinositol-3-kinase (PI3K)-AKT- mammalian target of rapamycin (mTOR) pathway. The PI3K-AKT-mTOR pathway is activated by various growth factor receptors such as HER2, fibroblast growth factor receptor 1 (FGFR1), insulin-like growth factor 1 R (IGF1R) among others. PI3K proteins are recruited to the plasma membrane, leading to phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 recruits to the membrane the AKT kinases that, once activated by PDK1 and mTORC2 phosphorylation, are able to phosphorylate TSC2 and negatively regulate the activity of the kinase mTOR. mTORC1 also phosphorylates and activates S6K. Also shown are few examples of PI3K-AKT-mTOR inhibitors in clinical trials.

Figure 2.

Proposed model of the phosphatidylinositol-3-kinase (PI3K)-estrogen receptor (ER) crosstalk. Estrogen activates nuclear ER known as the genomic pathway and membrane ER known as the non-genomic pathway. Membrane ER can associate with growth factor signaling components including PI3K. Activation of PI3K pathway activates its main effector AKT. After activation, AKT goes to the nucleus where it encounters nuclear substrate such as the H3K4 mono-and di-menthyltransferase KMT2D, an important regulator of nuclear ER. AKT phosphorylates KMT2D at S1331 to attenuate KMT2D function, inducing a loss of binding of KMT2D to ER target genes and a suppression of ER-dependent transcription (genomic pathway). Upon PI3Kα inhibition, AKT is no longer active and cannot phosphorylate KMT2D. KMT2D induces mono- and dimethylation of H3K4, is recruited to ER target loci and activates ER-dependent transcription (AKT-dependent mechanism). A target gene of ER is the PI3K effector SGK1. Upon PI3Kα inhibition, ER upregulates SGK1 transcription. Elevated SGK1, in turn, directly phosphorylates KMT2D at S1331, attenuating its function and subsequent ER activity as a negative repression feedback loop (SGK-dependent mechanism). ER-dependent increase of SGK1 upon PI3Kα inhibition in transient and may only be active few hours after PI3K pathway inhibition, while the overall ER-response can be sustained.