Identification of Pro-Differentiation p53 Target Genes and Evaluation of Expression in Normal and Malignant Mammary Gland
Abstract
Tumor stem cell theory implies that causative lesions underlying human malignancies occur and are harbored in multi-potent progenitors with retained proliferative capacity and a prolonged lifespan. Transcriptional profiling of human breast cancers has identified five distinct subtypes of which the basalepithelial subtype is most aggressive, correlates with poor prognosis, and lacks established molecular targets such as ER, PR and He2-overexpression. These tumors display a high degree of cellular heterogeneity suggesting that they may arise as the result of unregulated self-renewal in a multipotent cell. Clinically basal epithelial tumors are recognized by their negativity for ER, PR and He2, suggesting that the identification and validation of markers that definitively define this subtype will improve the diagnosis of these tumors. We present evidence that nestin, a previously-described neural progenitor marker is expressed in basal epithelia of the normal human mammary gland. Co-localization studies indicate two distinct populations of nestin-positive cells; one that expresses cytokeratin 14 and p63 and another that expresses desmin. Oncogenic transformation of a mammary progenitor cell culture model leads to increased expression of nestin. Immunohistochemical analysis of basal-epithelial breast tumors indicates robust expression of nestin, and CK14, punctate expression of p63, and low-to-undetectable levels of desmin expression. Nestin was not detected in other breast cancer sub-types, indicating selectivity for basal-epithelial breast tumors including those known to carry BRCA1 mutations. These studies coupled to the established role for p63 in the preservation of self-renewal suggest that basal breast tumors display biochemical features of mammary progenitors. Ectopic delta-N-p63 could block retinoic acid induced differentiation in embryonic carcinoma cells NT2/D1, and preserve transcript level of nestin post RA treatment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2009
- Accession Number
- ADA587700
Entities
People
- Hua Li
- James Direnzo
- Pratima Cherukuri
Organizations
- Geisel School of Medicine