Abstract
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.
Highlights
Triple-negative breast cancer (TNBC), which is largely synonymous with the basal-like molecular subtype of breast cancer, accounts for 10–15% of all breast-cancer cases[1]
These clinical results suggest that understanding and targeting these additional mechanisms of phosphatidylinositol-3-OH kinase (PI3K) pathway regulation and/or complementary pathways will be important for optimizing therapeutic strategies for TNBC patients
Consistent with the observed effect of SOX4 on multiple oncogenic signaling pathways, we recently showed that SOX4 is an essential regulator of PI3K/Akt signaling in basal-like tumors[5]
Summary
Triple-negative breast cancer (TNBC), which is largely synonymous with the basal-like molecular subtype of breast cancer, accounts for 10–15% of all breast-cancer cases[1]. While PIK3CA, which encodes for the oncogenic p110α catalytic subunit of the kinase, is the most commonly mutated gene in breast cancer[3], activating mutations occur at a low incidence (~9%) in basal-like tumors suggesting that other mechanisms contribute to altered signaling in these tumors[3,9]. Consistent with this argument, multi-platform genomic analyses have identified copy-number alterations or mutations in repressors of PI3K signaling including PTEN (35%) as well as mutations in known drivers of the pathway including EGFR (7%), ERBB2 (4%), IGFR1 (2%), and others in basal-like tumors[3,6]. SOX4 is a well-established oncogene and a member of the SOX
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