Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive, HER2-negative breast cancer

Abstract

Endocrine therapy is a crucial treatment for estrogen receptor-positive (ER+) breast cancer, with proven clinical benefits. However, adaptive mechanisms emerge in the tumor, causing resistance to endocrine therapy. A better understanding of resistance mechanisms is needed to overcome this problem and to develop new, precise treatment strategies. Accumulating genetic and cancer biological studies demonstrate the importance of understanding the PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2- breast cancer. PIK3CA (which encodes phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α) is frequently mutated in breast cancer, and 30% of advanced ER+ HER2- breast cancers have an activating PIK3CA mutation. AKT1 mutations (E17K) have been found in 1.4-8% of breast cancer patients. ER+ breast cancer patients preferentially demonstrate gain of CCND1 (cyclin D1; 58% in luminal B vs. 29% in luminal A) and CDK4 (25% in luminal B vs. 14% in luminal A) and loss of CDKN2A (p16) and CDKN2C (p18), which are negatively regulated with the cell cycle and are correlated with the CDK4/6/RB pathway. Abnormalities in PI3K/Akt/mTOR and CDK4/6/RB pathways due to genetic alterations result in deregulated kinase activity and malignant transformation. This review focuses on the recent reports of the essential role of PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2- breast cancer.

Keywords: Akt; Cyclin-dependent kinase (CDK) 4 and 6; Estrogen-positive; HER2-negtivebreast cancer; Mammalian target of rapamycin (mTOR); Phosphatidylinositol 3-kinases (PI3Ks); Retinoblastoma protein (RB).