PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

Abstract

Breast cancer is a serious health problem worldwide, representing the second cause of death through malignancies among women in developed countries. Population, endogenous and exogenous hormones, and physiological, genetic and breast-related factors are involved in breast cancer pathogenesis. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is a signaling pathway involved in cell proliferation, survival, invasion, migration, apoptosis, glucose metabolism and DNA repair. In breast tumors, PIK3CA somatic mutations have been reported, located in exon 9 and exon 20. Up to 40% of PIK3CA mutations are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) -negative in primary and metastatic breast cancer. HER2 is overexpressed in 20-30% of breast cancers. HER1, HER2, HER3 and HER4 are membrane receptor tyrosine kinases involved in HER signaling to which various ligands can be attached, leading to PI3K/AKT activation. Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy.

Keywords: HER2; PI3K/AKT/mTOR pathway; breast cancer; endocrine resistance; estrogen receptor-positive.

Figure 1

The PI3K/AKT/mTOR signaling pathway. PI3K is activated by the binding of ligands (insulin, growth factors, hormones) to RTKs, but also to GPCR (chemokines). Once activated, this protein kinase will catalyze the phosphorylation of PIP2 to PIP3. AKT is recruited to the plasma membrane where it undergoes two phosphorylation processes, one catalyzed by PDK1 at the level of threonine residue and the second reaction being catalyzed by mTORC2. Once activated by phosphorylation, AKT will phosphorylate other substances such as the mTOR complex, which will be associated in the end with protein synthesis and cell growth. Other phosphorylated substrates, such as GSK-3 and Fox01, will be inhibited, associated with cell proliferation and survival. PTEN is the major negative regulator of this signaling pathway involved in PIP3 dephosphorylation.

Figure 2

The PI3K/AKT/mTOR signaling pathway and breast cancer. The PI3K/AKT/mTOR signaling pathway is activated by ER, but also by EGFR, HER 2, IGFR1R, and FGFR1 at RTKs level. Once activated, protein kinase B or AKT inhibits TSC ½ by phosphorylation, further leading to the inhibition of Rheb and activation of mTORC1. This activation is associated with anti-apoptotic effects, increased gene expression, cell proliferation and angiogenesis. Everolimus and temsirolimus are two analogues of rapamycin that inhibit the activity of mTOR, especially mTORC1, but also mTORC2.