High Frequency of TP53 Mutation in BRCA1 and Sporadic Basal-like Carcinomas but not in BRCA1 Luminal Breast Tumors

Institut Curie, Centre de Recherche, Paris, France.
Cancer Research (Impact Factor: 9.33). 02/2009; 69(2):663-71. DOI: 10.1158/0008-5472.CAN-08-1560
Source: PubMed


Breast tumors with a germ-line mutation of BRCA1 (BRCA1 tumors) and basal-like carcinoma (BLC) are associated with a high rate of TP53 mutation. Because BRCA1 tumors frequently display a basal-like phenotype, this study was designed to determine whether TP53 mutations are correlated with the hereditary BRCA1 mutated status or the particular phenotype of these tumors. The TP53 gene status was first investigated in a series of 35 BRCA1 BLCs using immunohistochemistry, direct sequencing of the coding sequence, and functional analysis of separated alleles in yeast, and compared with the TP53 status in a series of 38 sporadic (nonhereditary) BLCs. Using this sensitive approach, TP53 was found to be frequently mutated in both BRCA1 (34 of 35, 97%) and sporadic (35 of 38, 92%) BLCs. However, the spectrum of mutation was different, particularly with a higher rate of complex mutations, such as insertion/deletion, in BRCA1 BLCs than in the sporadic group [14 of 33 (42%) and 3 of 34 (9%), [corrected] respectively; P = 0.002]. Secondly, the incidence of TP53 mutations was analyzed in 19 BRCA1 luminal tumors using the same strategy. Interestingly, only 10 of these 19 tumors were mutated (53%), a frequency similar to that found in grade-matched sporadic luminal tumors. In conclusion, TP53 mutation is highly recurrent in BLCs independently of BRCA1 status, but not a common feature of BRCA1 luminal tumors.

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    • "Recently, it has been suggested that phosphorylation of p53 at threonine 18 (T18) by TTK may contribute to the post-mitotic checkpoint, which arrests cells in G1 phase and therefore prevents further polyploidization [57]. Similarly to TNBC tumors, in which TP53 gene is frequently mutated [58], the three TNBC cell lines used in this study are also mutated for TP53 ( This may explain why we observed, following TTK depletion, a higher percentage of aneuploid cells in TNBC cell lines compared to normal cells that seem to arrest in G1, in agreement with a previous study [57]. "
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    ABSTRACT: Triple-negative breast cancer (TNBC) represents a subgroup of breast cancers (BC) associated with the most aggressive clinical behavior. No targeted therapy is currently available for the treatment of patients with TNBC. In order to discover potential therapeutic targets, we searched for protein kinases that are overexpressed in human TNBC biopsies and whose silencing in TNBC cell lines causes cell death. A cohort including human BC biopsies obtained at Institut Curie as well as normal tissues has been analyzed at a gene-expression level. The data revealed that the human protein kinase monopolar spindle 1 (hMPS1), also known as TTK and involved in mitotic checkpoint, is specifically overexpressed in TNBC, compared to the other BC subgroups and healthy tissues. We confirmed by immunohistochemistry and reverse phase protein array that TNBC expressed higher levels of TTK protein compared to the other BC subgroups. We then determined the biological effects of TTK depletion by RNA interference, through analyses of tumorigenic capacity and cell viability in different human TNBC cell lines. We found that RNAi-mediated depletion of TTK in various TNBC cell lines severely compromised their viability and their ability to form colonies in an anchorage-independent manner. Moreover, we observed that TTK silencing led to an increase in H2AX phosphorylation, activation of caspases 3/7, sub-G1 cell population accumulation and high annexin V staining, as well as to a decrease in G1 phase cell population and an increased aneuploidy. Altogether, these data indicate that TTK depletion in TNBC cells induces apoptosis. These results point out TTK as a protein kinase overexpressed in TNBC that may represent an attractive therapeutic target specifically for this poor prognosis associated subgroup of breast cancer.
    PLoS ONE 05/2013; 8(5):e63712. DOI:10.1371/journal.pone.0063712 · 3.23 Impact Factor
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    • "The frequency of complex mutations in the CNS metastatic lesions is higher than that in either of the series of primary carcinomas. The frequency of complex mutations is reported to be higher in basal subtype breast cancers, including cases arising in carriers of germ-line BRCA1 mutations (Holstege et al, 2009; Manié et al, 2009). In our series of CNS metastases, 7 out of 10 TNBC contained missense rather than complex mutations. "
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    ABSTRACT: Brain metastasis from breast cancer is usually associated with a poor prognosis and early death. Alteration of p53 may contribute to malignant progression by abrogation of apoptosis induced by oncogene activation and by acquisition of gain-of-function properties, which promote tumour aggression. Mutation in TP53 occurs at high frequency in carcinomas of the lung and gastro-intestinal tract, but is much less frequent, at 25%, in primary breast cancer. The frequency of TP53 alteration in the central nervous system (CNS) metastatic breast cancer is not known. In all, 23 cases of histologically confirmed CNS metastatic breast cancer were identified and the coding sequence of TP53 determined. TP53 was also sequenced in two control series of primary breast carcinomas from independent clinical centres. We demonstrate a strikingly high frequency of TP53 mutation in the CNS metastatic lesions with an over-representation of complex mutations (non-sense/deletions/insertions). Complex mutations occur in metastatic lesions in both triple-negative breast cancer and hormone receptor/HER2-positive cases. Analysis of paired primary carcinomas and brain metastatic lesions revealed evidence for both clonal selection and generation of new mutations (missense and complex) in progression from a primary breast carcinoma to brain metastasis. Mutation in TP53 is the most common genetic alteration reported during metastasis to the brain in breast cancer.
    British Journal of Cancer 12/2011; 106(2):397-404. DOI:10.1038/bjc.2011.464 · 4.84 Impact Factor
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    • "Tumors were considered TP53 mutant when (i) more than 15% of the yeast colonies were red (ii) analysis using the split versions of the test could identify the defect in the 5′ or 3′ parts of the gene, and (iii) sequence analysis from mutant yeast colonies could identify an unambiguous genetic defect (mutation, deletion, splicing defects) [46]. FASAY provided a major contribution to the analysis by revealing several TP53 mutations not detected by direct sequencing, principally in samples highly contaminated with stromal cells [47, 48]. "
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    ABSTRACT: The p53 wild-type protein plays an important role in cells as is shown by its fine regulation at different levels. Since its discovery, numerous mutations have been described. In breast cancers, p53 is mutated in almost 30% of cases, with a higher frequency in some tumor subtypes. TP53 mutation is reported to be a factor for good prognosis in some studies, while in others it is a factor for poor prognosis. The explanation for these different results could be linked to the fact that the studies were performed on different tumor types and with different therapy regimens.
    BioMed Research International 05/2011; 2011(1):284584. DOI:10.1155/2011/284584 · 2.71 Impact Factor
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