||5R01CA081078-04 Interpret this number
||Boston Medical Center
||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
Quantitative analysis of allele imbalance supports atypical ductal hyperplasia lesions as direct breast cancer precursors.
Larson PS, de las Morenas A, Cerda SR, Bennett SR, Cupples LA, Rosenberg CL
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.
Larson PS, Schlechter BL, de las Morenas A, Garber JE, Cupples LA, Rosenberg CL
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.
Larson PS, de las Morenas A, Bennett SR, Cupples LA, Rosenberg CL
Am J Pathol, 2002 Jul;161(1), p. 283-90.