p53 in breast cancer subtypes and new insights into response to chemotherapy

Abstract

Despite an obvious central role of p53 in the hallmarks of cancer, TP53 status is not yet used for the management of breast cancer. Recent findings may lead to reconsider the role of p53 in breast cancer. TP53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas. Their distribution is highly linked to molecular tumor subtypes found in 26% of luminal tumors (17% of luminal A, 41% of luminal B), in 50% of HER2 amplified tumors, in 69% of molecular apocrine breast carcinomas and in 88% of basal-like carcinomas. The type of mutation is linked to the tumor subtype with higher frequency of base-pair substitutions in luminal tumors, whereas molecular apocrine and basal-like tumors present much higher frequency of complex mutations (deletions/insertions). The timing of TP53 mutation also depends on the tumor subtype, being the first important event in luminal tumors but occurring after PTEN loss in basal-like tumors. Regarding response to cytotoxic chemotherapy, the situation is far from the p53-dependent apoptosis paradigm with subsequent clinical response. We reported that TP53 mutated non inflammatory locally advanced breast carcinomas had a high rate of complete pathological response to dose-dense doxorubicin-cyclophosphamide chemotherapy, while TP53 wild-type (WT) tumors never achieved complete response. Using human breast cancer xenograft models, we suggested that this could be due to the induction of senescence in TP53 WT tumor cells. A recent work confirmed these findings in MMTV-Wnt1 mammary tumors, showing that growth arrest and senescent phenotype, not apoptosis, were induced in TP53 WT tumors following doxorubicin treatment, while lack of arrest in mutant tumors resulted in aberrant mitoses, cell death and a superior clinical response. Furthermore, in ER positive (ER(+)) breast tumors, it has been recently reported that ER represses the p53-mediated apoptotic response induced by DNA damage. Taken together, these data can help to better understand p53-mediated response to doxorubicin-based chemotherapy in breast cancer: in ER(+) TP53 WT breast cancers, ER-induced inhibition of p53 apoptotic response would lead preferentially to tumor cell senescence and subsequent resistance to treatment. Conversely, in ER negative (ER(-)) TP53 mutated breast cancers, accumulation of genetic abnormalities would lead to mitotic catastrophe and subsequent better response. In view of these recent results, p53 impact in breast cancer should be reconsidered.

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

“…The predictive and prognostic value of TP53 status in various types of cancer has been the subject of several thousand studies with conflicting findings and limited clinical application, and a review of this literature is beyond the scope of this article (38)(39)(40). These discordant results are due to multiple causes, such as the methodology and strategy used to assess TP53 status, the heterogeneity of tumor types, the genetic background of the tumor, and the large number of different TP53 variants.…”

ID4 controls luminal lineage commitment in normal mammary epithelium and inhibits BRCA1 function in basal-like breast cancer

“…The BLBC subtype is enriched for patients harbouring mutations in tumour suppressor protein 53 (TP53) and BRCA1 ( (Lakhani et al 2005, Turner et al 2007, Bertheau et al 2013) and reviewed in Mavaddat et al 2010). This subtype has been defined using molecular analysis of patient samples and represents a subset of the triplenegative subtype.…”

Analysis of polymorphisms in codons 11, 72 and 248 of TP53 in Brazilian women with breast cancer

“…Some types of alteration are clearly linked to higher frequency of substitutions, resulting in the production of p53 protein with potential new functions, such as p63 and p73 inactivation. Notably, molecular apocrine and basal-like tumors present a much higher frequency of complex mutations (deletions/ insertions) that often lead to a lack of p53 protein (Bertheau et al, 2013).…”