Mehta Gaurav A, Angus Steven P, Khella Christen A, Tong Kevin, Khanna Pooja, Dixon Shelley A H, Verzi Michael P, Johnson Gary L, Gatza Michael L
Department of Radiation Oncology, Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
NPJ Breast Cancer. 2021 Apr 9;7(1):40. doi: 10.1038/s41523-021-00248-2.
Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression.
PI3K/Akt信号通路失调是基底样或三阴性乳腺癌（TNBC）的一个主要特征。然而，在这类侵袭性肿瘤中，调节该信号通路的机制在很大程度上尚不清楚。在此，我们证明转录因子SOX4是TNBC中PI3K信号的关键调节因子。基因组和蛋白质组分析以及机制研究确定TGFBR2是SOX4的直接转录靶点，并证明TGFBR2是介导SOX4依赖性PI3K信号所必需的。我们进一步报道，在基底样肿瘤中均呈过表达的SOX4和SWI/SNF ATP酶SMARCA4形成了一种此前未报道的复合物，该复合物是维持TGFBR2调控区域开放染色质构象以介导TGFBR2表达和PI3K信号所必需的。总体而言，我们的研究结果阐明了SOX4和SMARCA4协同调节PI3K/Akt信号的机制，并表明该复合物可能在TNBC的发生和/或进展中起重要作用。
