p53 mutation in breast cancer. Correlation with cell kinetics and cell of origin

Abstract

Aim: Several studies have investigated the expression of the cytokeratins (CKs), vimentin, the epithelial growth factor receptor (EGFR), the oestrogen receptor (ER), and the progesterone receptor (PgR), in breast cancer, but no study has directly compared p53 mutations with these phenotypic and differentiation markers in the same case. The present study was designed to provide some of this information. Methods: The expression of the p53 and bcl-2 proteins was evaluated by immunohistochemistry in relation to phenotypic characteristics and cellular kinetic parameters (mitotic index and apoptotic index) in 37 cases of ductal carcinoma in situ (DCIS) and 27 cases of infiltrating ductal carcinoma (IDC) of the breast. In addition, p53 gene mutation was examined by polymerase chain reaction single strand conformation polymorphism analysis (SSCP). Results: Thirteen cases (eight DCIS and five IDC) showed expression of CK8, CK14, CK18, vimentin, and EGFR, consistent with a stem cell phenotype, whereas 44 cases (27 DCIS and 17 IDC) showed expression of CK8 and CK1, weak or negative expression of CK18, but were negative for vimentin and EGFR, consistent with a luminal cell phenotype. DCIS and IDC cases with a stem cell phenotype were ER/PgR negative and intermediately or poorly differentiated. In contrast, the cases with luminal cell phenotype were ER/PgR positive and well or intermediately differentiated. In addition, intermediately or poorly differentiated cases with a stem cell phenotype showed higher proliferative activity (per cent of MIB-l positive cells) than did intermediately or well differentiated cases with a luminal cell phenotype. Both DCIS and IDC cases with a stem cell phenotype were p53 positive and bcl-2 negative by immunohistochemistry. In IDC, p53 expression was associated with a reduction of both mitotic index and apoptotic index compared with DCIS. Most of the tumours showing a more differentiated phenotype (luminal) were p53 negative and bcl-2 positive. In these cases, cell kinetic parameters increased from DCIS to IDC. These data suggest the existence of subsets of DCIS and IDC that, because of their phenotypic characteristics, could be derived from subpopulations of normal breast cells having different control mechanisms of cell proliferation and neoplastic progression. Conclusions: These results are compatible with the hypothesis that the phenotype of the cell of origin constrains both tumour phenotype and the choice of genetic events; however, the occurrence of p53 mutants by chance during neoplastic transformation cannot be excluded.

High‐throughput protein expression analysis using tissue microarray technology of a large well‐characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses

“…These findings can be explained by the postulate that subsets of breast cancer exist that are either derived from different normal cell populations or differentiate along different pathways as a consequence of having different alterations in the control mechanisms of cell proliferation and hence neoplastic progression; this may be p53-dependent in the tumours with a less differentiated, basal phenotype and p53-independent in those tumours with a more differentiated, pure luminal form. The existence of p53 mutations by chance in the later subset cannot, however, be excluded, 29,30 as shown by our finding that occasional tumours in groups 1, 2, 3 and 6 exhibited p53 expression. This supports the suggestion that cell type-specific genetic pathways are maintained in distinct genetic evolutionary pathways in mammary carcinogenesis.…”

Correlation between cell cycle proteins and hMSH2 in actinic cheilitis and lip cancer

“…Defective MMR system is a very frequent genetic alteration in many malignancies, including squamous cell carcinoma, and recent studies have demonstrated these alterations in potentially malignant disorders, such as AC [33,35]. In addition, changes in system MMR genes can cause disorders in cell cycle proteins such as p53 [22]. Based on this, we performed the immunohistochemical analysis of cell cycle proteins p53 and p21 in the same sample used in our previous study [33] to verify if there is any relationship between the alterations in hMSH2 expression and the aforementioned cell cycle proteins in different stages of lip carcinogenesis.…”

Alterations of p53, Bcl-2, and hMSH2 protein expression in the normal breast, benign proliferative breast disease, in situ and infiltrating ductal breast carcinomas in the upper egypt

“…9,10 Several studies have proposed close interactions among p53, Bcl-2 and hMSh2 proteins during carcinogenesis. 3,7,9,11 This proposition is supported by two notions. First, p53 can inhibit Bcl-2 protein expression through p53-regulatory domain in the Bcl-2 gene.…”

“…34 Several studies reported that there is a relationship between MMR genes, oncogenes and TSGs during mammary carcinogenesis. 3,7,9,11 Interestingly, the concomitant expression of p53 and hMSH2 was seen in 11 cases. This finding suggests that p53; hMSH2 protein expression is regulated by a common mechanism.…”

“…In the ductal carcinomas, p53 gene is mutated with subsequent overexpression of p53 protein. [6][7][8] The Bcl-2 oncogene, an antiapoptotic molecule residing in the mitochondria, is also involved in mammary carcinogensis. 9,10 Several studies have proposed close interactions among p53, Bcl-2 and hMSh2 proteins during carcinogenesis.…”