A Genetic, Molecular, and Structural Analysis of Hormonal Carcinogenesis

Principal Investigator: PRESS, MICHAEL F
Program: BCRP
Proposal Number: BC030152
Award Number: W81XWH-04-1-0791
Funding Mechanism: Breast Cancer Center of Excellence Award
Partnering Awards:
Award Amount: $9,835,513.00


Background: Normal breast tissue development is regulated by female hormones, especially estrogen and progesterone. These hormones also play an important role in stimulating the development of breast cancer. However, studies of breast cancer in large populations and in populations of twins have shown that hormones alone do not fully account for all breast cancer risk. There also appears to be a significant genetic component to breast cancer risk. However, the genes and the alterations in these genes that are responsible for this component of increased breast cancer risk have not been identified or characterized. This Breast Cancer Center of Excellence (BCCOE) is designed to study genetic variation in genes that are responsible for mediating the primary hormonal effects in the breast.

Ideas to Be Tested: Genetic variations in genes that mediate responses to female hormones in the breast are responsible for a substantial proportion of breast cancer risk. This genetic variation leads to changes in the three-dimensional shape of the encoded mediator proteins and, therefore, changes in the function of these proteins.

Objective: Identify genetic variations in specific hormone mediator genes and characterize the molecular, structural and functional alterations associated with these genetic variants.

Specific Aims: A comprehensive, high throughput examination of the genes mediating hormonal carcinogenesis, including the entire cascade of proteins responsible for regulating breast responses to estrogen and progesterone, will be conducted to evaluate normal, inherited, genetic variations, referred to as genetic polymorphisms, and acquired mutations in the breast in order to assess the amount of variation present in these genes and to determine if this variation affects the structure of the proteins coded by these genes or the function of the encoded proteins. The specific aims are to (1) perform a systematic screen of the genes encoding proteins that regulate hormonal response to identify potentially important polymorphisms/mutations, and study the relationship between these variants and breast cancer risk in the multi-ethnic cohort; (2) determine the three-dimensional structures of important hormone receptor functional domains in association with proteins implicated in hormonal responsiveness and breast cancer including genetic variants of these genes; and (3) use functional assays to evaluate the significance of the structural and genetic data on receptor/cofactor activity and identify novel receptor-associated complexes.

Study Design: This BCCOE will accomplish these aims using molecular genetic, functional and structural methods. We will use high-throughput gene sequencing technologies to analyze the regulatory and entire coding regions of genes that determine hormone response and look for potentially relevant polymorphisms and mutations in breast cancer tissue and blood from women in a large multiethnic cohort. The three-dimensional structure of proteins having known genetic variation as well as those newly identified by this BCCOE will be characterized. Changes in functional activity associated with identified genetic variations will be assessed using a variety of methods. This multidisciplinary approach will permit a group of established investigators and breast cancer advocates to study a single pivotal problem in breast cancer that is at the interface of several sub-disciplines.

Significance: Because hormone receptors and their cofactors play critical roles in the ability of estrogen and progesterone to activate specific responses, relevant polymorphisms and mutations are likely to affect breast cancer risk, occurrence, and progression. Identification of such functionally relevant polymorphisms/mutations will (1) produce new diagnostic tools for assessing breast cancer risk, (2) provide important new clues to the specific molecular functions of the affected protein subunits, (3) identify new molecular targets for therapeutic intervention, and (4) characterize novel estrogen receptor protein binding sites that may lead to breast cancer therapeutics targeting specific pathways. Because there is still limited understanding about the specific functions of many of these cofactors, the identified polymorphisms/mutations will provide important opportunities to learn about the molecular functions of these proteins and thus their specific roles in breast cancer risk.