|Grant Number:||5R01CA081078-04 Interpret this number|
|Primary Investigator:||Rosenberg, Carol|
|Organization:||Boston Medical Center|
|Project Title:||Genetic Abnormalities Early on the Path of Breast Cancer|
DESCRIPTION: Breast cancer is a genetic disease, but little is known about genetic abnormalities central to the first steps of tumorigenesis. Identifying these abnormalities may be critical to understand breast cancer risk and development, and to create new detection and treatment strategies. To elucidate these important early abnormalities, Dr. Rosenberg and colleagues developed a powerful system using microsatellite markers to investigate archival specimens of human breast tissue. It was demonstrated that "benign" and even histologically normal breast tissue could contain monoclonal, genetically aberrant cell populations. Based on these studies, it has been hypothesized, first, that breasts of certain individuals may contain widespread genetic abnormalities, i.e., field cancerization. To test this hypothesis, this research team will examine normal-appearing breast tissue from 2 groups at risk for a field defect: 1) premenopausal women with sporadic breast cancer; and 2) premenopausal women with a heritable, constitutional mutation in BRCA1 or BRCA2 genes. Dr. Rosenberg speculates that these tissues will contain an increase in genetic abnormalities, especially allele imbalance (AI) suggestive of loss of heterozygosity (LOH), compared with control reduction mammoplasty (RM) specimens. Further, the patterns of abnormalities in the groups may differ, suggesting distinct pathways of carcinogenesis. Second, it is hypothesized that sites of frequent LOH in histologically normal breast epithelium may identify candidate genes critical to the earliest stages of breast tumorigenesis. Candidate genes to be tested must fulfill tow criteria: 1) location near frequent sites of LOH in normal-appearing tissue (likely indicating the existence of a tumor-suppressor gene in the vicinity) and 2) a role in carcinogenesis, maintenance of genomic stability, or growth control documented in the literature. To test their potential role in breast carcinogenesis, Dr. Rosenberg will then examine these genes' expression in normal-appearing, proliferative and malignant breast tissue. Pilot studies identified the first, paradigmatic, example of this strategy: p57KIP2, a cyclin dependent kinase inhibitor (CDKI) which inhibits cyclin/cdk complexes and arrests cells in G1. To test this hypothesis, three aims are proposed. Aim 1 is to determine whether field cancerization exists in histologically normal breast epithelium of women less than 40 years of age with sporadic breast cancer or with heritable, constitutional BRCA1 or BRCA2 mutations, compared to control tissue. Aim 2 is to identify candidate genes acting early in breast carcinogenesis. Aim 3 is to test candidate genes to determine if their inactivation contributes to the transition from normal to transformed breast epithelial cells. Studies are outlined with the first identified candidate, p57KIP2. These investigations should illuminate genetic events instrumental in the initial steps of breast carcinogenesis.
Quantitative analysis of allele imbalance supports atypical ductal hyperplasia lesions as direct breast cancer precursors.
Authors: Larson PS, de las Morenas A, Cerda SR, Bennett SR, Cupples LA, Rosenberg CL
Source: J Pathol, 2006 Jul;209(3), p. 307-16.
Allele imbalance, or loss of heterozygosity, in normal breast epithelium of sporadic breast cancer cases and BRCA1 gene mutation carriers is increased compared with reduction mammoplasty tissues.
Authors: Larson PS, Schlechter BL, de las Morenas A, Garber JE, Cupples LA, Rosenberg CL
Source: J Clin Oncol, 2005 Dec 1;23(34), p. 8613-9.
Loss of heterozygosity or allele imbalance in histologically normal breast epithelium is distinct from loss of heterozygosity or allele imbalance in co-existing carcinomas.
Authors: Larson PS, de las Morenas A, Bennett SR, Cupples LA, Rosenberg CL
Source: Am J Pathol, 2002 Jul;161(1), p. 283-90.