The aim of this article is to discuss mutant p53 as a possible therapeutic target and biomarker for breast cancer. Disruption of p53 gene function seems to have a pivotal role in carcinogenesis. Tumor cell death following exposure to radiotherapy occurs by apoptosis and is a p53 dependent event. Tp53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast. Targeting p53 and myc proteins with drugs gave positive. Enhanced breast cancer progression by mutant p53 is inhibited by. In a metaanalysis of 4,683 patients with breast cancer, the overexpression of p53 was correlated with poor outcome in premenopausal women treated with tamoxifen after chemotherapy. The p53 breast cancer trial p53b the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. As expected, we observed a negative correlation between the expression levels of pp2c. Inflammatory breast cancer ibc is a rare and aggressive form of breast cancer. Downregulation of bcl2 by p53 in breast cancer cells. The p53 pathway in breast cancer breast cancer research.
Tp53 mutations are common in breast cancer and are typically associated with more aggressive tumor characteristics, but little is known about. Mutant p53 accumulation in human breast cancer is not an. This study was designed to determine whether p53 protein accumulation in breast cancers correlates with p53 gene mutation, with survival, and with five. The frequency of mutation in p53 is, however, lower in breast cancer than in other solid tumours. An expression signature for p53 status in human breast. We have identified and analyzed 41 mutations in p53 in sporadic breast tumors from 6 unselected breast cancer patients and estimate that approximately. In breast cancer, p53 mutations are associated with worse overall. The life history of cancer cells encompasses a series of genetic missteps in which normal cells are progressively transformed into tumor cells that invade surrounding tissues and become malignant. In breast cancer, p53 mutation is associated with more aggressive disease and worse overall survival. Most of the existing preclinical breast cancer xenograft models used to study metastasis to lung or bone involve injecting human cancer cell lines that have been extensively cultured ex vivo into the tail vein or left ventricular chamber of the heart, respectively. Germline mutations in p53 occur in a high proportion of individuals with the lifraumeni cancer susceptibility syndrome, which confers an increased risk of breast cancer.
One study found that p53 and myc proteins were key to the survival of chronic myeloid leukaemia cml cells. The tumor suppressor p53 is lost or mutated in about half of all human cancers, and in those tumors in which it is wildtype, mechanisms exist to prevent its activation. Tp53 status and response to treatment in breast cancers. Breast cancers that develop in women carrying a brca1 germline mutation are more aggressive and confer a worse overall survival than. In breast cancer, p53 mutations are associated with worse overall and. Inhibiting mdm2 activity increases the extent of p53 stabilization in some, but not all, breast cancer cell lines. Tp53 is the most frequently mutated gene in cancer, including breast cancer. This enables p53 deficient tumor cells with dna damage to continue. Consequently, careful planning is required in targeting p21waf1cip1 expression for therapy of breast cancer patients. Tp53 mutations are the most frequent genetic alterations in breast cancer, observed in 30% of breast carcinomas. Previous studies on the role of tp53 mutation in breast cancer treatment response and survival are contradictory and inconclusive, limited by. Tp53 p53 is the most frequently mutated gene in invasive breast cancer.
The p53 gene and its role in cancer verywell health. Genetic basis for p53 overexpression in human breast cancer. It is considered that all those, who inherit only one functional copy of the p53 gene from their parents, are more likely to become a prey of cancer as they are predisposed to cancer. To achieve this, all three methods were carried out on a cohort of aggressive breast. This low number of p53 mutations did not allow us to find a significant statistical association between p53 isoform expression and p53 mutation. Pdf interaction of werner and bloom syndrome genes with. It is estimated that p53 mutations are the most frequent genetic event in human cancers, accounting for. Our results reveal that gtse1 played a key role in the progression of breast cancer, indicating that gtse1 could serve as a novel biomarker to aid in the assessment of the prognosis of breast cancer. Suppression of p53 in human breast cancer cells is shown to lead to increased cxcr5 chemokine receptor gene expression and activated cell migration in response to chemokine cxcl. Lai et al analyzed exons 58 of the p53 gene in the tumors from 199 breast cancer patients. The p53 gene tp53 is a gene that is mutated in many cancers, and is the most common gene mutation found in cancer cells. The aim of this investigation was to examine the ability of the yeastbased functional assay, the functional analysis for the separation of alleles in yeast fasay, to detect p53 mutations in breast cancers when compared with immunohistochemistry and automated sequencing of the whole p53 gene exons 111. Alteration to the p53 tumor suppressor gene is associated with more aggressive disease in breast cancer, as evidenced by the shortened survival of patients with mutation.
Pdf p53 mutation remains the most common genetic change identified in human neoplasia. This implies an important role for p53 inactivation in mammary carcinogenesis, and the structure and expression of p53 has been widely studied in breast cancer. We retrospectively analyze the expression of p53 as a prognostic marker to predict pathological complete response and survival in patients with ibc. Clinicopathological and epidemiological significance of. Contribution of p53 to metastasis cancer discovery.
To determine whether the inhibitory effect of om on p53 is limited to the h3922 cell line or is a common response of breast cancer cells to om, the effect of om on p53 protein expression was examined in two other ominhibited breast cancer cell lines, mcf7 and mdamb231. The p53 pathway in breast cancer pubmed central pmc. Downregulation of bcl2 by p53 in breast cancer cells subrata haldar,2 massimo negrini, maria monne, silvia sabbioni, and carlo m. Higher parp1 protein levels and par proteins were detected in mtp53 r273h than in wildtype p53 expressing pdx samples. Breast cancer survival predicted by tp53 mutation status differs. Pdf p53 plays a key role in mediating cell response to various stresses, mainly by inducing or repressing a number of genes involved in cell cycle. Gtse1 is involved in breast cancer progression in p53. The clinical correlation between therapeutic resistance and p53 mutation has been studied since 1990s. Breast cancer, gtse1, p53, cell cycle, prognosis background breast cancer is one of the major malignancies worldwide 1, 2.
Complexes formed by mutant p53 and their roles in breast cancer arianna bellazzo,1 daria sicari,1,2 elena valentino,1,2 giannino del sal,1,2 licio collavin1,2 1national laboratory cib lncib, area science park, trieste, italy. The p53 tumor suppressor is a critical regulator of tissue homeostasis, and its inactivation at the gene or protein level confers cellular properties conducive for oncogenesis and cancer progression. Estrogen receptor prevents p53dependent apoptosis in. Hence, mutant p53 is often associated with a poor prognosis for cancers of the breast 23. Croce jefferson cancer institute and jefferson cancer center, thomas jefferson university, philadelphia, pennsylvania 19107 abstract bd2 and p53 gene products have been both linked to programmed cell death pathways. Manumycin polyketides act as molecular glues between ubr7. Nrf2 and p53 signaling were similarly coordinated in normal breast epithelial tissue and hormonenegative ductal carcinoma in situ lesions but were uncoupled in triplenegative breast cancer tnbc, a subtype in which p53 is usually mutated.
In their studies, pairwise haplotypes of these three polymorphisms were estimated. Using the integrated model, we correlated the extent of this uncoupling in tnbc cell lines. Genetic basis for p53 overexpression in human breast cancer ncbi. Mutant p53 in cancer therapythe barrier or the path. The presence of mutation, with or without accompanying loss of heterozygosity loh, was an early finding in cell lines and primary breast cancers, establishing p53. In duplication in intron 3 of p53, is associated with an increased conclusion, our study indicates the importance of inherited colorectal cancer risk and reduced p53 mrna levels 30. Improving the detection of p53 mutations in breast cancer. Nuclear expression of p53 protein in breast cancer correlates with more aggressive tumors. Staining of p53 and parp1 in breast cancer tmas and comparison with the tcga database indicated a higher doublepositive signal in basallike breast cancer than in luminal a or luminal b subtypes.
Thus, p21waf1cip1 is regarded as a protein with a dual behavior, as its expression might cause potential benefits or dangerous effects in breast cancer. Although mutated in 3035% of all cases, p53 is mutated in approximately 80% of triplenegative tn tumors i. Data obtained from in vitro experiments suggest that mutations to different structural and functional domains of p53 may give rise to different effects on its biological activities, notably transactivational and apoptotic. Mutations of the tumor suppressor gene p53 have been identified in breast cancer cell lines, and some breast carcinomas are detectable by immunohistochemical assay because of p53 protein accumulation. Brca1, p53, and breast cancer inheritance of a mutation in the brca1 gene confers a 5085% lifetime risk for women of developing breast cancer and a 1545% lifetime risk of developing ovarian cancer 1, 2. One hundred seven patients with ovarian cancer were included in.
Mutations in p53 occur in 50% of human cancers 1, 2, and the mutational status of p53 is prognostic in many malignancies. Listing a study does not mean it has been evaluated by the u. Tab1tak1p38 mapk pathway in wildtype p53 multidrugresistant bc. Sequencing of the complete coding region of the tp53 gene in breast cancer from a cohort of 316 patients revealed that p53 mutation is associated with significantly worse prognosis and resistance to adjuvant systemic therapy bergh et al. These results shed light on the possible development of new approaches to inhibit the malignancy of p53 mutations. Recent findings may lead to reconsider the role of p53 in breast cancer. The expression of p53 tumor suppressor gene in breast. Tp53 codes for a transcription factor, p53, that initiates transcription of genes involved in cell cycle arrest, cellular senescence, apoptosis, metabolism, dna repair and other processes following cellular stress. Mutation of p53 at codon 175 from an arginine to a histidine confers resistance to chemotherapeutic agents such as cisplatinum and etoposide. The data indicate that missense mutant p53 stabilization is a complex and variable process in human breast cancers that associates with disease characteristics but is unrelated to structural or functional properties. Most prominent among the regulators disrupted in cancer cells are two tumor suppressors, the retinoblastoma protein rb and the p53 transcription factor. To generalize the conclusions, the analysis should be extended to di erent types of cancer datasets. We investigated the association between p53 protein accumulation and p53 mutations detected in benign breast tissue and risk of subsequent breast cancer.
Breast cancer survival predicted by tp53 mutation status. In breast cancer, p53 mutation is associated with more. By contrast, figure 2 p53 mutant breast cancer patients expressing p53g have diseasefree survival and overall survival comparable to that of patients bearing wildtype wt p53 breast cancer. Breast cancer is the most frequently diagnosed malignancy in women, and mutations in the. Unlike er, pr and her2, the prognostic and predictive value of p53 in breast cancer, especially in visceral breast cancer, is still under discussion. Complexes formed by mutant p53 and their roles in breast. Since p53 is located on chromosome 17p and loss of heterozygosity is thought to play a role in its activation, we sought to determine whether p53 is aberrantly expressed in epithelial ovarian cancer.
Overexpression and mutation of p53 in epithelial ovarian. The gene is a type of tumor suppressor gene that codes for a protein that inhibits the development and growth of tumors. Inheritance of certain germ line haplotypes consisting of three biallelic polymorphisms of p53 has been proposed as a risk factor for breast cancer and colorectal cancer a. A tumor suppressor gene like p53 is there, to stop the formation of tumors. Changes, both genetic and epigenetic, have been identified in regulators of p53 activity and in some downstream. Using activitybased protein profiling abppbased chemoproteomic platforms, we show that members of the manumycin family of polyketides, which bear multiple potentially reactive sites, target c374 of the putative e3 ligase ubr7 in breast cancer cells to impair breast cancer pathogenicity through engaging in molecular glue interactions with. The impact of p53 in predicting clinical outcome of breast. Despite an obvious central role of p53 in the hallmarks of cancer, tp53 status is not yet used for the management of breast cancer.
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