Abstract
We recently established c-Abl as a potent suppressor of triple-negative breast cancer (TNBC) progression through its reactivation of a p53:p21 signaling axis coupled to senescence. Moreover, we observed co-expression of p53 and c-Abl to be essential for normal mammary epithelial cell physiology, as this relationship is lost upon breast cancer progression. Cytoplasmic c-Abl activity is markedly increased in some TNBCs and contributes to disease progression; however, the mechanisms underlying these events remain largely unknown. In addressing this question, we show here that c-Abl is predominantly restricted to the cytoplasm of human MDA-MB-231 TNBC cells, and to the nucleus of human MCF-7 luminal A cells. TTK is a mitotic protein kinase that phosphorylates c-Abl on Thr735, thereby creating a recognition binding motif for 14-3-3 adaptor proteins in response to oxidative stress. By interrogating the METABRIC database, we observed a significant correlation between p53 expression and that of c-Abl and TTK in basal-like breast cancers. Moreover, heterologous expression of TTK in MCF-7 cells significantly stimulated their growth in part via a c-Abl-dependent mechanism. Conversely, depleting TTK expression in MDA-MB-231 cells not only inhibited their organoid growth in 3D-cultures, but also sensitized them to the tumor suppressing activities of c-Abl independent of its subcellular localization. Moreover, we show that mutant p53 forms cytoplasmic complexes with c-Abl, thereby dictating the subcellular localization of c-Abl and the sensitivity of MDA-MB-231 cells to Imatinib. In response to nutrient deprivation, c-Abl:p53 complexes readily accumulate in the nucleus, resulting in the hyperactivation of c-Abl and initiation of its anti-tumor activities. Collectively, we identified a novel mutant p53:c-Abl cytoplasmic signaling complex that promotes MDA-MB-231 cell growth and highlights the contextual cues that confer oncogenic activity to c-Abl in breast cancer.
Highlights
The specific context in which the tumor suppressing activities of c-Abl are hijacked to drive breast cancer progression is largely unknown
We established p53 expression as an essential determinant for the correlation between c-Abl and TTK expression across all breast cancer subtypes. This correlation was most relevant in basal-like breast cancers, whose loss of TTK expression inhibited their proliferation and sensitized them to DPH-mediated c-Abl activation
Engineering luminal A cells to overexpress TTK induced their growth in a mechanism that was in part dependent upon the expression of c-Abl. These results are interesting with respect to the importance of p53 expression in regulating that of TTK and c-Abl, as this correlation predicts that depletion of TTK expression would correlate with an increase in c-Abl expression and vice versa
Summary
The specific context in which the tumor suppressing activities of c-Abl are hijacked to drive breast cancer progression is largely unknown. We previously demonstrated the ability of c-Abl to inhibit oncogenic TGF-β signaling in TNBCs,[10] an event requiring c-Abl to activate an autocrine TGF-β1-dependent Smad2:Smad1/5/8 signaling axis that reactivated p53 expression and led to the induction of a p21-dependent senescent reaction.[11] Interestingly, c-Abl and p53 are co-expressed in normal mammary tissues, we observed both proteins to be expressed in a highly discordant manner in human breast cancers. The extent to which p53 status correlates with the tumor activities of c-Abl in breast cancer remains unknown. We hypothesized that the ability of c-Abl to suppress TNBCs development and progression is dependent upon its co-expression with wild-type p53. A corollary states that breast cancers, which escape c-Ablmediated suppression, do so through discordant expression of c-Abl and wild-type p53, or alternatively through mutational inactivation of p53 to disrupt its normal functions. The objective of this study was to determine whether mutant p53 expression contributed either directly or indirectly to the loss of c-Abl mediated suppression of TNBC
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