Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
Department of Medical Biology, University of Quebec at Trois-Rivieres, Trois-Rivieres, Quebec, Canada.
Mol Cancer Res. 2018 Jun;16(6):1046-1058. doi: 10.1158/1541-7786.MCR-17-0593. Epub 2018 Mar 15.
Breast cancer is a leading cause of death in women worldwide. Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB are observed in a large number of breast cancers. In recent years, aberrant activation of Transcriptional coactivator with PDZ binding motif (TAZ) and its paralog Yes-associated protein (YAP) have also been found to be important for breast cancer development and progression. However, whether PI3K interacts with YAP/TAZ during mammary tumorigenesis is unknown. Through a systematic gain-of-function screen for kinases involved in mammary tumorigenesis, we identified PIK3CB as a transformation-inducing kinase in breast cells. We further determined that PIK3CB positively regulates YAP and TAZ to promote transformation and inhibit mammary cell death PIK3CB coexpression with TAZ, rather than PIK3CB or TAZ alone, in human MCF10A nontumorigenic mammary cells is sufficient for tumor formation in mice Interestingly, we also determined that PIK3CA-H1047R enhances YAP and TAZ activity in mammary tumorigenesis Mechanistically, the regulation of YAP/TAZ by both PIK3CA and PIK3CB occurs through multiple signaling pathways including LATS-dependent and LATS-independent pathways. Therefore, in this study, we determine that PI3K and YAP/TAZ interact to promote breast cancer cell transformation. This study provides the first evidence that the Hippo pathway effectors TAZ and YAP are critical mediators of PI3K-induced mammary tumorigenesis and synergistically function together with PI3K in transformation of mammary cells. These findings may provide a novel rationale for targeting YAP/TAZ alone or in combination with PI3K inhibitors for breast cancer therapy in the future. .
乳腺癌是全球女性死亡的主要原因。在大量乳腺癌中观察到 PI3K 催化亚基 PIK3CA（例如 H1047R）的活跃突变和其同源物 PIK3CB 的扩增。近年来，转录共激活因子与 PDZ 结合基序（TAZ）及其旁系同源物 Yes 相关蛋白（YAP）的异常激活也被发现对乳腺癌的发展和进展很重要。然而，PI3K 在乳腺肿瘤发生过程中是否与 YAP/TAZ 相互作用尚不清楚。通过对参与乳腺肿瘤发生的激酶进行系统的功能获得筛选，我们鉴定出 PIK3CB 是乳腺细胞中的转化诱导激酶。我们进一步确定 PIK3CB 正向调节 YAP 和 TAZ 以促进转化并抑制乳腺细胞死亡。PIK3CB 与 TAZ 的共表达，而不是 PIK3CB 或 TAZ 单独表达，足以在人 MCF10A 非致瘤乳腺细胞中形成肿瘤 在小鼠中。有趣的是，我们还确定 PIK3CA-H1047R 在乳腺肿瘤发生中增强了 YAP 和 TAZ 的活性。从机制上讲，PI3KCA 和 PIK3CB 对 YAP/TAZ 的调节通过包括 LATS 依赖和 LATS 非依赖途径在内的多种信号通路发生。因此，在这项研究中，我们确定 PI3K 和 YAP/TAZ 相互作用以促进乳腺癌细胞转化。这项研究首次提供了证据，表明 Hippo 途径效应物 TAZ 和 YAP 是 PI3K 诱导的乳腺肿瘤发生的关键介质，并且与 PI3K 一起协同作用于乳腺细胞的转化。这些发现可能为未来针对 YAP/TAZ 或与 PI3K 抑制剂联合治疗乳腺癌提供新的依据。
