The rebel angel: mutant p53 as the driving oncogene in breast cancer

Abstract

Breast cancer is the most frequent invasive tumor diagnosed in women, causing over 400 000 deaths yearly worldwide. Like other tumors, it is a disease with a complex, heterogeneous genetic and biochemical background. No single genomic or metabolic condition can be regarded as decisive for its formation and progression. However, a few key players can be pointed out and among them is the TP53 tumor suppressor gene, commonly mutated in breast cancer. In particular, TP53 mutations are exceptionally frequent and apparently among the key driving factors in triple negative breast cancer -the most aggressive breast cancer subgroup-whose management still represents a clinical challenge. The majority of TP53 mutations result in the substitution of single aminoacids in the central region of the p53 protein, generating a spectrum of variants ('mutant p53s', for short). These mutants lose the normal p53 oncosuppressive functions to various extents but can also acquire oncogenic properties by gain-of-function mechanisms. This review discusses the molecular processes translating gene mutations to the pathologic consequences of mutant p53 tumorigenic activity, reconciling cell and animal models with clinical outcomes in breast cancer. Existing and speculative therapeutic methods targeting mutant p53 are also discussed, taking into account the overlap of mutant and wild-type p53 regulatory mechanisms and the crosstalk between mutant p53 and other oncogenic pathways in breast cancer. The studies described here concern breast cancer models and patients-unless it is indicated otherwise and justified by the importance of data obtained in other models.

Fig. 1.

Frequency and structure of p53 missense alterations in breast cancer. (A) Human p53 domain structure with indicated frequency (percent bars) of missense changes in TP53 found in spontaneous (above) or Li–Fraumeni-associated (below) breast cancer. The five most frequently changed codons are indicated by numbers and residue names. The codon 280 marked with (*) is included due to the widespread use of the MDA-MB-231 cell line, bearing R280K p53, as a model for invasive breast cancer (see Table I). (B) Structural position of residues affected by most frequent missense-mutation-related changes in the DNA-binding domain (DBD) of human p53. DNA-contacting Arginine side chains are colored red (R280 is marked with * as in A), residues whose change affects DBD folding in p53 ‘structural mutants’ are colored green. The position of the DBD-stabilizing Zinc (Zn) atom is also indicated. Derived from Protein Data Bank (PDB) ID: 1TUP (33). (C) Structural position of the residues most frequently altered in Li–Fraumeni breast cancer—Arginine 337 (side chains colored blue)—in the oligomerization domains of human p53 tetramer. Derived from PDB ID: 1C26 (163).

Fig. 2.

Mutant p53 involvement in processes associated with breast cancer development. Mutant p53 is known to affect multiple oncogenic processes (,. Although different oncogenic mechanisms overlap during tumorigenesis, here they are arbitrarily divided into mechanisms indispensable for early tumorigenesis at the level of single-cell biochemistry (green), mechanisms supporting multicellular tumor mass growth (orange), and features necessary for metastasis to secondary sites (red). The asterisks (*) indicate oncogenic mechanisms known to be important for breast cancer, linked to p53 gain-of-function in other tumors, but not yet directly tested for mutant p53 dependence in mammary carcinoma cells or mouse models. See text for detailed information and references.

Fig. 3.

Mutant p53 as the hub of oncogenic pathways in breast cancer. The activity of mutant p53 is regulated through upstream signal transducers as well as regulators of transcription, stability and structure. Its biological effects are mediated by direct transcriptional activity and through association with downstream protein effectors. These mechanisms are interconnected (small arrows), especially downstream of mutant p53, as most proteins bound directly are transcription regulators. The figure includes only the factors/processes that were found to affect the tumorigenic features of breast cancer models or patients and target genes found to be directly regulated by mutant p53. *PTMs—Posttranslational Modifications may be affected by upstream factors and may influence downstream effects of mutant p53. †TopBP1 is implicated as a coordinator protein of mutant p53 GOF exerted via NF-Y, p63 and p73.