BRCA1 regulation in breast cancer: a rat mammary model

Institution: University of Southern California
Investigator(s): Donna Williams-Hill, Ph.D. -
Award Cycle: 1996 (Cycle II) Grant #: 2KB-0232 Award: $368,159
Award Type: New Investigator Awards
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle



Initial Award Abstract (1996)
Studies of Japanese atomic bomb survivors showed that the risk of developing breast cancer was highest among women who were irradiated at 0-9 years of age, while the risk of those exposed during puberty was significantly lower. Women who were over the age of forty at the time of the atomic blast were found to be at only minimally increased risk for breast cancer. More recent studies have found that inherited genes associated with the development of breast cancer, such as BRCA1, have been more frequently identified in young women (20-29) with breast cancer. Taken together, these observations suggest that the younger a female is when she is exposed to a breast cancer causing agent, the more likely she is to develop the disease. How or why this is is unknown.

Understanding the role of breast cancer associated genes during breast development may be key to designing more effective interventions and preventive strategies for women in all risk groups. However, dissecting such complex interrelationships in humans is extremely difficult for both practical and ethical reasons. One alternative is to utilize animal models to systematically analyze the factors associated with breast cancer risk, and mechanisms related to the cause of this disease. The rat mammary model provides a well characterized system for answering questions regarding how breast cancer develops in humans. The development of the mammary glands, and changes that occur in the breast during pregnancy, when mother rats nurse, and following weaning, are very similar to comparable events in humans, but occur over much shorter time frames. Using this model, we propose to study one of the genes thought to act as an inhibitor of tumors in the breast, BRCA1. Our studies will focus on how this gene acts in the mammary gland as it matures and during the development of breast cancer. The information gained will contribute to understanding whether there is a critical time in a female's life when breast cancer is most likely to begin, with the final goal of finding ways to prevent this disease.


Final Report (1999)
Studies of Japanese atomic bomb survivors have shown that the risk of developing breast cancer was highest among women who were irradiated before ten years of age, while the risk of those exposed during puberty was significantly lower. Women over the age of forty were only minimally susceptible. More recent epidemiological studies indicate that inherited genes associated with the development of breast cancer, such as BRCA1, have more frequently been identified in women at an early age at onset. Taken together, these observations suggest that the physiology of the immature and developing breast may contribute to breast cancer susceptibility and subsequent pathogenesis of the disease. However, the mechanisms underlying these important observations are unknown.

Inbred strains of rat vary in their susceptibility to mammary cancer. The Copenhagen (Cop) and Wistar-Kyoto (Wky) are resistant to both spontaneous and induced mammary carcinogenesis. Sprague-Dawley (SD) and Wistar Furth strains are susceptible to mammary cancer while the Fisher (F344) strain has intermediate susceptibility. These strains have been used in the development of a rat mammary transplantation assay that has provided critical information regarding the initiation and progression of mammary cancer in rats and for analyzing factors affecting breast cancer pathogenesis. The BRCA1 gene has been cloned in the rat and probes have been developed for molecular analysis of this gene. In addition, the development of the mammary glands, the states of pregnancy and lactation and gland involution following weaning involve repeated rounds of cell replication, differentiation (maturation) and death during reproductive cycles. Thus, the rat mammary system can be used to analyze the genes related to breast cancer on mammary gland proliferation. Finally, as in humans, rat mammary glands are susceptible to radiation induced cancer development. Mammary carcers can be induced by available X-ray sources and the latency period and rate of tumor induction subsequently correlated to developmental and molecular (i.e. BRCA1 gene expression) parameters. Using this model, we analyzed the temporal and hormonal regulation of the breast cancer suppressor gene BRCA1 in the mammary gland and its effect on mammary cancer induction. This approach allowed us to address questions concerning 1) the role of BRCA1 in normal mammary gland development 2) the role of BRCA1 in breast cancer susceptibility and 3) the possible role of hormones in regulation of BRCA1. The information gained will contribute both to the understanding of breast cancer pathogenesis and also aid in the development of prophylactic interventions.

Molecular determinants of response of locally advanced breast cancer to 5-FU and Radiation
Periodical:Proceedings of the American Association for Cancer Research
Index Medicus: Proc Am Assoc Cancer Res
Authors: Formenti S, Park S, Slaonga JM, Williams-Hill D, et al
Yr: 1998 Vol: 39 Nbr: Abs: 1279 Pg:

Is BRCA1 expression during development related to carcinogenic susceptibility?
Periodical:Proceedings of the American Association for Cancer Research
Index Medicus: Proc Am Assoc Cancer Res
Authors: Williams-Hill DM, Hill CK
Yr: 1997 Vol: 38 Nbr: Abs: 3134 Pg:

BRCA-1 Regulation in the mammary gland of rat strains that differ in their carcinogenic susceptibility
Periodical:Proceedings of the American Association for Cancer Research
Index Medicus: Proc Am Assoc Cancer Res
Authors: Williams-Hill DM, and Hill CK
Yr: 1998 Vol: 39 Nbr: Abs: 209 Pg:

BRCA1 and BRCA2 gene expression in esophageal tumors and adjoining normal tissues
Periodical:Proceedings of the American Association for Cancer Research
Index Medicus: Proc Am Assoc Cancer Res
Authors: Park JM, Salonga D, Danenberg K, Kelsen D, Danenberg PV, and Williams-Hill DM
Yr: 1998 Vol: 39 Nbr: Abs: 210 Pg: