Division of Breast and Endocrine, Department of Surgery, Cancer Center, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
Breast Cancer. 2018 Jul;25(4):392-401. doi: 10.1007/s12282-017-0812-x. Epub 2017 Oct 31.
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.
内分泌治疗是雌激素受体阳性（ER+）乳腺癌的重要治疗方法，具有明确的临床获益。然而，肿瘤中会出现适应性机制，导致对内分泌治疗产生耐药性。为了克服这一问题并开发新的、精准的治疗策略，需要更好地了解耐药机制。越来越多的遗传和癌症生物学研究表明，了解 PI3K/Akt/mTOR 和 CDK4/6/RB 通路在 ER+HER2-乳腺癌中的重要性。PIK3CA（编码磷脂酰肌醇-4,5-二磷酸 3-激酶催化亚单位α）在乳腺癌中经常发生突变，30%的晚期 ER+HER2-乳腺癌存在激活的 PIK3CA 突变。AKT1 突变（E17K）在 1.4%-8%的乳腺癌患者中被发现。ER+乳腺癌患者优先表现出 CCND1（细胞周期蛋白 D1；在 luminal B 中为 58%，在 luminal A 中为 29%）和 CDK4（在 luminal B 中为 25%，在 luminal A 中为 14%）的获得以及 CDKN2A（p16）和 CDKN2C（p18）的缺失，这些基因的失活与细胞周期负相关，与 CDK4/6/RB 通路相关。由于遗传改变导致 PI3K/Akt/mTOR 和 CDK4/6/RB 通路的异常，会导致激酶活性失调和恶性转化。本综述重点介绍了 PI3K/Akt/mTOR 和 CDK4/6/RB 通路在 ER+HER2-乳腺癌中的重要作用的最新研究进展。
