Complexes formed by mutant p53 and their roles in breast cancer

Abstract

Breast cancer is the most frequently diagnosed malignancy in women, and mutations in the tumor suppressor p53 are commonly detected in the most aggressive subtypes. The majority of TP53 gene alterations are missense substitutions, leading to expression of mutant forms of the p53 protein that are frequently detected at high levels in cancer cells. P53 mutants not only lose the physiological tumor-suppressive activity of the wild-type p53 protein but also acquire novel powerful oncogenic functions, referred to as gain of function, that may actively confer a selective advantage during tumor progression. Some of the best-characterized oncogenic activities of mutant p53 are mediated by its ability to form aberrant protein complexes with other transcription factors or proteins not directly related to gene transcription. The set of cellular proteins available to interact with mutant p53 is dependent on cell type and extensively affected by environmental signals, so the prognostic impact of p53 mutation is complex. Specific functional interactions of mutant p53 can profoundly impact homeostasis of breast cancer cells, reprogramming gene expression in response to specific extracellular inputs or cell-intrinsic conditions. The list of protein complexes involving mutant p53 in breast cancer is continuously growing, as is the number of oncogenic phenotypes in which they could be involved. In consideration of the functional impact of such complexes, key interactions of mutant p53 may be exploited as potential targets for development of therapies aimed at defusing the oncogenic potential of p53 mutation.

Keywords: cancer-cell homeostasis; mutant p53 gain of function; protein–protein interactions; targeted therapy.

Figure 1

Mutant p53 (mutp53) interacts with various transcription factors (TFs) to reprogram gene expression in cancer cells. Notes: (A) Mutp53 forms a complex with NFY, p300, PELP1, and TopBP1 to control expression of genes involved in cell proliferation and in resistance to DNA-damaging drugs.– (B) Mutp53 binds with YAP and NFY on the promoters of genes involved in cell growth and proliferation; both mechanical inputs and activation of the mevalonate pathway control formation and activity of this protein complex.–, (C) By interacting with SREBP2, mutp53 controls expression of enzymes involved in the mevalonate pathway, promoting cholesterol and fatty-acid biosynthesis, sustaining disruption of mammary-tissue architecture, and inhibiting mechanisms of mutp53 degradation.–,, (D) By interacting with NRF2, mutp53 controls expression of multiple subunits of the proteasome, alleviating proteotoxic stress and accelerating turnover of cell-cycle inhibitors. (E) In a complex with HSF1, mutp53 controls expression of chaperones and heat-shock proteins that in turn promote mutp53 stability. (F) Mutp53 may interact with additional transcription factors, potentially controlling expression of different gene sets, to mediate its oncogenic gain of function.

Figure 2

Mutant p53 (mutp53) forms complexes with cytoplasmic mediators of signal transduction. Notes: (A) Mutp53 binds and inhibits the tumor suppressor DAB2IP in the cytoplasm of breast cancer cells, reducing TNF-induced activation of the proapoptotic ASK1–JNK axis, simultaneously promoting activation and of proinvasive NFκB transcription factor. (B) Mutp53 inhibitory action on DAB2IP promotes insulin-induced activation of the PI3K–Akt pathway, enhancing cell proliferation and invasion in hormone-independent breast and prostate cancers. (C) Mutp53 binds the AMPKα subunit and inhibits AMPK activation upon energy stress. This leads to increased anabolic growth of tumor cells and cancer progression. (D) Mutp53 binds the monomeric GTPase Rac1, protecting it from SENP1-mediated de-SUMOylation. SUMOylated Rac1 is more active, sustaining tumor growth and dissemination.

Figure 3

Therapeutic approaches targeting mutant p53 (mutp53) protein complexes. Notes: Pharmacological approaches aimed at disrupting mutp53 complexes represent an appealing strategy for cancer therapy. Such approaches involve stabilizing mutp53 to restore its wild-type functions, reducing mutp53 levels by disrupting mechanisms of mutp53 accumulation, counteracting mutp53 activity by targeting specific mutp53 modulators, preventing or disrupting oncogenic complexes with specific target proteins, and inhibiting mediators or pathways downstream of mutp53 protein complexes (see text for details).