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Missense mutations in the TP53-binding domain predominate, and >30% of these occur in just eight codons. Dominant negative properties of mutant p53, taken together with the mutation susceptibility of the nucleotides in the codon, are believed to explain the prevalence of specific mutations, including hot spots. We analyzed multiple tumor types and found no difference in clinical characteristics or survival between patients with dominant negative p53 mutant tumors and those with TP53 mutations that are predicted to be non-dominant negative. The rate tumors underwent loss of heterozygosity in these respective mutation classes was nearly identical, suggesting that presence of stable, mutant protein with predicted dominant negative activity does not reduce selective pressure to inactivate the wild-type allele. Our data suggest all inactivating mutations of TP53 are equal, and the frequency of dominant negative, hot spot mutations is likely driven more by the relative mutability of the DNA at specific codons.

Background Previous studies on the role of TP53 mutation in breast cancer treatment response and survival are contradictory and inconclusive, limited by the use of different endpoints to determine clinical significance and by small sample sizes that prohibit stratification by treatment. Methods We utilized large datasets to examine overall survival according to TP53 mutation status in patients across multiple clinical features and treatments. Results Confirming other studies, we found that in all patients and in hormone therapy-treated patients, TP53 wild-type status conferred superior 5-year overall survival, but survival curves crossed at 10 or more years. In contrast, further stratification within the large dataset revealed that in patients receiving chemotherapy and no hormone therapy, wild-type TP53 status conferred remarkably poor overall survival. This previously unrecognized inferior survival is consistent with p53 inducing arrest/senescence instead of apoptosis. Addition of hormone therapy to chemotherapy improved survival notably in patients with TP53 wild-type tumors, but not mutant, suggesting hormone therapy could eradicate arrested/senescent cells. Testing this, we found that estrogen receptor-positive, TP53 wild-type breast cancer cells that were made senescent by doxorubicin treatment were sensitive to tamoxifen. Conclusions The poor survival of chemotherapy-treated patients with TP53 wild-type tumors may be improved by strategies to eliminate senescent cells, including the addition of hormone therapy when appropriate. Electronic supplementary material The online version of this article (10.1186/s13058-018-1044-5) contains supplementary material, which is available to authorized users.

Insulin-like growth factors (IGFs) regulate breast cancer cell proliferation, protect cells from apoptosis, and enhance metastasis. In this study, we examined the IGF signaling pathway in two breast cancer cell lines selected for metastatic behavior. LCC6 was selected for growth as an ascites tumor in athymic mice from parental MDA-MB-435 cells (435P). The MDA-231BO cell line was derived from osseous metastases that formed after intracardiac injection of the MDA-MB-231 cell line in athymic mice. Compared to the parental cell lines, IGF-I treatment enhanced IRS-2 phosphorylation over IRS-1 in the metastatic variants. IGF-I stimulated cell migration in the variant cells, but not in the parental cells. To determine the role for IRS-2 in IGF-mediated motility, we transfected MDA-231BO cells with an anti-sense IRS-2 construct. Transfected cells had decreased levels of IRS-2 with diminished IGF-mediated motility and anchorage independent growth when compared to control cells. However, adherence to fibronectin was enhanced in the transfected cells compared to MDA-231BO cells. Our data show that breast cancer cells selected for metastatic behavior in vivo have increased IRS-2 activation and signaling. In these cells, IGF-I enhances cell adhesion and motility suggesting that IRS-2 may mediate these aspects of the malignant phenotype.