Amplification of SOX4 promotes PI3K/Akt signaling in human breast cancer

Abstract

Purpose The PI3K/Akt signaling axis contributes to the dysregulation of many dominant features in breast cancer including cell proliferation, survival, metabolism, motility and genomic instability. While multiple studies have demonstrated that basal-like or triple negative breast tumors have uniformly high PI3K/Akt activity, genomic alterations that mediate dysregulation of this pathway in this subset of highly aggressive breast tumors remain to be determined. Methods In this study, we present an integrated genomic analysis based on the use of a PI3K gene expression signature as a framework to analyze orthogonal genomic data from human breast tumors, including RNA expression, DNA copy number alterations, and protein expression. In combination with data from a genome-wide RNA-mediated interference screen in human breast cancer cell lines we identified essential genetic drivers of PI3K/Akt signaling. Results Our in silico analyses identified SOX4 amplification as a novel modulator of PI3K/Akt signaling in breast cancers and in vitro studies confirmed its role in regulating Akt phosphorylation. Conclusions Taken together, these data establish a role for SOX4 mediated PI3K/Akt signaling in breast cancer and suggest that SOX4 may represent a novel therapeutic target and/or biomarker for current PI3K-family therapies.

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…Additionally, PRLR/Jak2/STAT5 is the main signaling pathway for activation in mammary gland, and PRLR-triggered pro-tumorigenic pathways in BC include the PI3K/AKT pathway [172]. As well, numerous studies have shown that IRS4, CDK12, SPC24, Mfng, Transgelin 2, STX3, SOX4, PAK4, TPX2, MEG3 and miR-21, -93, -106b, -130b, -214, -361-5p, -489, -511, -564 as well as lncRNA-HOTAIR and MALAT1 regulate tumorigenesis, proliferation, apoptosis, invasion, migration, paclitaxel resistance or anti-Her2 therapy (trastuzumab) resistance of BC cells through PI3K/AKT pathway [173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191]. And then, PI3K/AKT inhibitors have gained wide attentions, and a large number of clinical trials may have provided tremendous promises in the treatment of BC patients (shown in Tables 2 and 3).…”

SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond

“…While the molecular regulation of most other SOX proteins remains poorly defined, further connectivity to the PI3K/AKT axis has been proposed for SOX4. In mammary carcinoma, elevated SOX4 expression promotes PI3K/AKT signaling [107], while glioblastoma cell cycle progression involves SOX4-dependent modulation of AKT and p53 [108]. Interestingly, SOX4 and SOX2 proteins only distantly relate within the SOX family [3], but the two proteins show nearly overlapping occurrence in human cancers [48].…”

The Enigmatic Helicase DHX9 and Its Association With the Hallmarks of Cancer

“…SOX4 has been proposed as an oncogene because of its frequent overexpression in cancers, including prostate and breast cancer. SOX4 also has involvement in proliferative signaling pathways such as Wnt and PI3K [65][66][67]. In PCa, SOX4 forms a nuclear complex with plankoglobin following induction of Wnt signaling.…”