Distinct tumor protein p53 mutants in breast cancer subgroups

Abstract

Tumor protein p53 (TP53) is mutated in approximately 30% of breast cancers, but this frequency fluctuates widely between subclasses. We investigated the p53 mutation status in 572 breast tumors, classified into luminal, basal and molecular apocrine subgroups. As expected, the lowest mutation frequency was observed in luminal (26%), and the highest in basal (88%) tumors. Luminal tumors showed significantly higher frequency of substitutions (82 vs. 65%), notably A/T to G/C transitions (31 vs. 15%), whereas molecular apocrine and basal tumors presented much higher frequencies of complex mutations (deletions/insertions) (36 and 33%, respectively, vs. 18%). Accordingly, missense mutations were significantly more frequent in luminal tumors (75 vs. 54%), whereas basal tumors displayed significantly increased rates of TP53 truncations (43 vs. 25%), resulting in loss of function and/or expression. Interestingly, as basal tumors, molecular apocrine tumors presented with a high rate of complex mutations, but paradoxically, these were not associated with increased frequency of p53 truncation. As in luminal tumors, this could reflect a selective pressure for p53 gain of function, possibly through P63/P73 inactivation. Collectively, these observations point not only to different mechanisms of TP53 alterations, but also to different functional consequences in the different breast cancer subtypes.With more than one in ten women estimated to develop breast cancer in her life, breast cancer is the most frequent cancer of women. Breast cancer is a heterogeneous disease, usually classified into Luminal-A, Luminal-B, Basal-like, Normal-like and human epidermal growth factor receptor 2 (HER2)-enriched subclasses.1 However, at the moment, there is not a strict parallelism between subclasses and therapy, and in clinical practice, patient diagnosis is routinely based on estrogen receptor alpha (ERa) progesterone receptor and HER2 statuses. A simplified molecular classification based on ERa, androgen receptor (AR) and forkhead box protein A1 (FOXA1) expression has been recently proposed.2,3 The first class, ERaþ, corresponds to luminal tumors which present active estrogen signaling. The second class (ERa-, AR-and FOXA1-tumors), called basal, shows much higher proliferative and aggressive behaviors. Tumors of the third class (ERa-, ARþ and/or FOXA1þ), called molecular apocrine, present androgen and estrogen signaling despite ERa-status, and frequently overexpress HER2. 2Tumor protein p53 (TP53) encodes a multifunction transcription factor whose loss promotes tumor formation. 4 It is the most commonly mutated gene in human cancers. Approximately, 30% of breast cancers display TP53 mutation, but this frequency fluctuates from more than 80% in basallike to less than 15% in luminal-A subgroups.5 Mutations result from misrepair of DNA damages. The main mutation types are substitutions and complex mutations. Substitutions correspond to the replacement of a nucleotide pair by a different pair. They result essentially from replication of mismatch...

Clinicopathologic and Demographic Evaluation of Triple-Negative Breast Cancer Patients among a Turkish Patient Population: a Single Center Experience

“…This rate is approximately 80% in basal-like cancers while it is reported to be less than 15% in luminal breast cancers (Sørlie et al, 2001). In a study evaluating 572 patients, the rate of p 53 mutation was 26% and 88% in the luminal group and the basal-like group, respectively (Durnay et al, 2013). The rate of p 53 mutation was 44% and 28% in the TNBC group and the NTNBC group, respectively, and the difference between these two groups were statistically significant (p=0.001).…”

Phosphorylation of NTRK1 at Y674/Y675 induced by TP53-dependent repression of PTPN6 expression: A potential novel prognostic marker for breast cancer

“…Overall, these results suggest that in estrogen receptor-positive tumors, [55][56][57][58][59] These studies have also shown that in a given population, the incidence of luminal A tumors is 48-58%, luminal B tumors is 19-25%, triple negative tumors is 11-23%, and HER2-positive tumors is 5-11%. [55][56][57][58][59] Based on this type of classification, analysis of the frequencies of the sub-groups in our data set has shown that 129 (50%) are luminal A, 75 (29%) are luminal B, 37 (14%) are triple negative, and 15 (6%) are HER2-positive tumors. There was insufficient information for 52 samples to classify them into one of the sub-groups, as either ER, PgR, or HER2 expression data were not available.…”

Molecular aspects of breast cancer resistance to drugs (Review)

“…This has enabled the distinction of different molecular subtypes in breast cancer (25), and their identification make it possible to select a specific treatment strategy and to better predict the prognosis (6). Approximately 70% of all breast cancers diagnosed in the USA are ER + (22,36).…”

“…A molecular form includes genetic analysis as chromosomes 6, 7, 21 or molecular biotechnology, using biological markers as estrogen receptor (ER In addition, other factors can be analyzed that can be originated in the cancer cell itself as mutations in p53, EGFR or influenced by microenvironment as pH and MMP9 (6,7). According to some gene expression profile studies five different subtypes have been identified (8,9) …”