Placental Cadherin and the Basal Epithelial Phenotype of BRCA1-Related Breast Cancer

Abstract

Purpose: BRCA1-related breast cancer frequently has a basal epithelial phenotype, and P-cadherin is a basal marker. We undertook a detailed evaluation of the relationship among P-cadherin, prognostic markers in breast cancer, and outcome. Experimental Design: This study was restricted to 292 cases of first primary invasive breast cancer diagnosed in Ashkenazi Jewish women between 1980 and 1995. All available blocks were stained for P-cadherin, and 261 were included in the final statistical analyses, including 27 germ line BRCA1 mutation carriers and 8 BRCA2 mutation carriers. Descriptive analyses were done followed by survival analyses and a Poisson regression analysis. Results: P-cadherin was present in 80 of the 261breast cancers (31%) and was more frequently present in tumors that have a basal epithelial phenotype [i.e., high-grade, estrogen receptor^and KIP1 (p27 Kip1)^negative tumors, with expression of cytokeratin 5/6, cyclin E,TP53, and presence of BRCA1 mutations and vascular nests (all P < 0.001)]. In a univariate survival model, expression of P-cadherin was associated with a relative risk (RR) of death from breast cancer at a 10-year follow-up of 2.9 (95% confidence interval, 1.8-4.7; P < 0.0001) and was a predictor of poor univariate survival in both lymph node^negative and^positive breast cancers. In a multivariate analysis, the effect of P-cadherin levels was not independent of other basal-related markers. Multivariable interaction modeling showed that P-cadherin positivity was highly predictive of a poor prognosis in small, node-negative breast cancers (RR, 7.1; P = 0.006). Conclusions: P-cadherin is a marker for basal-like breast cancers and is strongly associated with the presence of a BRCA1 mutation. It is an adverse prognostic factor, particularly in small, node-negative breast cancers.

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

“…5 More recently, a subgroup of lobular carcinomas has been shown to express high-molecular-weight cytokeratins, 41 however it remains to be determined whether these cases truly show a basal-like transcriptome. The majority of basal-like breast cancers lack or show low levels of ER and PR, lack HER2 protein overexpression and HER2 gene amplification, whereas they express genes and proteins usually found in 'basal'/myoepithelial cells of the normal breast including high-molecular-weight cytokeratins (5/6, 14 and 17), 17,19,21,42 P-cadherin, 43 caveolins 1 and 2, 44,45 nestin, 46 aB crystallin, 47,48 CD109, 49,50 and EGFR 17 and, in a minority of cases, harbor EGFR gene amplification 51 or aneusomy. 52 p53 immunohistochemical expression or TP53 gene mutations is observed in up to 85% of cases, 53,54 and alterations of the pRB and p16 G1/S cell-cycle checkpoint are remarkably prevalent in these cancers.…”

Pathology of hereditary breast cancer

“…BRCA2 tumours were shown to have higher expression of the cell cycle proteins cyclin D1, cyclin D3, p27, p16, p21, CDK4, CDK2 and CDK1. 35 Association with 'basal' phenotype As BRCA1-associated cancers are often triple negative (ERÀ, PgRÀ, HER2À), it is not surprising that a high proportion show a 'basal' phenotype (expression of basal/myoepithelial markers such as CK5/6, CK14, SMA, EGFR, P-cadherin and caveolin 1) 17,22,36,37 ( Figure 1f). This is not a significant feature of BRCA2/BRCAX-related breast cancers, in that, the frequency is not higher than in sporadic cancers.…”

BRCA1 mutations contribute to cell motility and invasion by affecting its main regulators

“…2); in contrast, the expression of P-cadherin, Caveolin-1 and Id-1 are downregulated in BB2-E6/E7-BRCA1-restroed cells in comparison with BB2-E6/E7 cells. Several studies reported a strong correlation between BRCA1-mutated genes and P-cadherin as well as Caveolin-1 expression in human breast cancer cells; [17][18][19] however, the association between E-cadherin expression and BRCA1 mutations in breast cancer tissue is not confirmed. 17 In this study, we demonstrate for the first time that the 3450delCAAG-BRCA1-mutation deregulates the expression patterns of P-cadherin, Caveolin-1 as well as E-cadherin; moreover, BRCA1 restoration reinstates the expression of these genes to the normal state in human mammary epithelial cells (Suppl.…”