Dirican Ebubekir, Akkiprik Mustafa
Department of Medical Biology, School of Medicine, Marmara University, Istanbul, Turkey.
Tumour Biol. 2017 Mar;39(3):1010428317695529. doi: 10.1177/1010428317695529.
Breast cancer is the most commonly diagnosed cancer among women in Turkey and worldwide. It is considered a heterogeneous disease and has different subtypes. Moreover, breast cancer has different molecular characteristics, behaviors, and responses to treatment. Advances in the understanding of the molecular mechanisms implicated in breast cancer progression have led to the identification of many potential therapeutic gene targets, such as Breast Cancer 1/2, phosphatidylinositol 3-kinase catalytic subunit alpha, and tumor protein 53. The aim of this review is to summarize the roles of phosphatidylinositol 3-kinase regulatory subunit 1 (alpha) (alias p85α) and phosphatase and tensin homolog in breast cancer progression and the molecular mechanisms involved. Phosphatase and tensin homolog is a tumor suppressor gene and protein. Phosphatase and tensin homolog antagonizes the phosphatidylinositol 3-kinase/AKT signaling pathway that plays a key role in cell growth, differentiation, and survival. Loss of phosphatase and tensin homolog expression, detected in about 20%-30% of cases, is known to be one of the most common tumor changes leading to phosphatidylinositol 3-kinase pathway activation in breast cancer. Instead, the regulatory subunit p85α is a significant component of the phosphatidylinositol 3-kinase pathway, and it has been proposed that a reduction in p85α protein would lead to decreased negative regulation of phosphatidylinositol 3-kinase and hyperactivation of the phosphatidylinositol 3-kinase pathway. Phosphatidylinositol 3-kinase regulatory subunit 1 protein has also been reported to be a positive regulator of phosphatase and tensin homolog via the stabilization of this protein. A functional genetic alteration of phosphatidylinositol 3-kinase regulatory subunit 1 that results in reduced p85α protein expression and increased insulin receptor substrate 1 binding would lead to enhanced phosphatidylinositol 3-kinase signaling and hence cancer development. Phosphatidylinositol 3-kinase regulatory subunit 1 underexpression was observed in 61.8% of breast cancer samples. Therefore, expression/alternations of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog genes have crucial roles for breast cancer progression. This review will summarize the biological roles of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog in breast cancer, with an emphasis on recent findings and the potential of phosphatidylinositol 3-kinase regulatory subunit 1 and phosphatase and tensin homolog as a therapeutic target for breast cancer therapy.
乳腺癌是土耳其和全球女性中最常被诊断出的癌症。它被认为是一种异质性疾病，有不同的亚型。此外，乳腺癌具有不同的分子特征、行为和对治疗的反应。对乳腺癌进展所涉及分子机制理解的进展，已导致鉴定出许多潜在的治疗性基因靶点，如乳腺癌1/2、磷脂酰肌醇3-激酶催化亚基α和肿瘤蛋白53。本综述的目的是总结磷脂酰肌醇3-激酶调节亚基1（α）（别名p85α）和磷酸酶及张力蛋白同源物在乳腺癌进展中的作用以及所涉及的分子机制。磷酸酶及张力蛋白同源物是一种肿瘤抑制基因和蛋白。磷酸酶及张力蛋白同源物拮抗在细胞生长、分化和存活中起关键作用的磷脂酰肌醇3-激酶/AKT信号通路。在约20%-30%的病例中检测到的磷酸酶及张力蛋白同源物表达缺失，是导致乳腺癌中磷脂酰肌醇3-激酶途径激活的最常见肿瘤变化之一。相反，调节亚基p85α是磷脂酰肌醇3-激酶途径的重要组成部分，有人提出p85α蛋白减少会导致磷脂酰肌醇3-激酶负调节减少和磷脂酰肌醇3-激酶途径过度激活。据报道，磷脂酰肌醇3-激酶调节亚基1蛋白还通过稳定该蛋白而成为磷酸酶及张力蛋白同源物的正调节因子。磷脂酰肌醇3-激酶调节亚基1的功能性基因改变导致p85α蛋白表达减少和胰岛素受体底物1结合增加，会导致磷脂酰肌醇3-激酶信号增强，从而促进癌症发展。在61.8%的乳腺癌样本中观察到磷脂酰肌醇3-激酶调节亚基1表达不足。因此，磷脂酰肌醇3-激酶调节亚基1和磷酸酶及张力蛋白同源物基因的表达/改变对乳腺癌进展起着关键作用。本综述将总结磷脂酰肌醇3-激酶调节亚基1和磷酸酶及张力蛋白同源物在乳腺癌中的生物学作用，重点是近期研究结果以及磷脂酰肌醇3-激酶调节亚基1和磷酸酶及张力蛋白同源物作为乳腺癌治疗靶点的潜力。
