Androgen Receptor Gene and p21 Gene in Breast Cancer

Institution: University of Southern California
Investigator(s): Wei Wang, M.D. -
Award Cycle: 2005 (Cycle 11) Grant #: 11FB-0133 Award: $34,293
Award Type: Postdoctoral Fellowship
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle



Initial Award Abstract (2005)
Introduction: Androgens, which are usually thought of as male hormones, have many important functions in the female body. These functions are both indirect, through acting as a source of estrogen production, and direct, through binding to the androgen receptor (AR). Accumulating evidence has suggested that in female breast, these two modes of action might lead to different outcomes. The indirect effect contributes to increased breast cancer risk, while the direct effect may be protective. The overall effect will be the balance between these two. In our recently-completed study among women with and without breast cancer, we incorporated a genetic marker (AR variant) to specifically examine the direct effect of androgens. Our study found a relationship between the stronger AR variant and a reduced breast cancer risk among women whose mother or sister(s) had been affected by breast cancer, supporting the postulated protective direct effect of androgens. However, our previous study was very small and included only African-American women. Data are still too sparse to determine which groups of women might be protected by androgens. Therefore we propose to reexamine this question in two larger studies that include three racial groups. Moreover, we will explore possible mechanisms of the protective effect of androgens by examining one specific protein (p21) which plays a very important role in controlling the growth and division of normal and cancer cells. This protein was chosen for study because androgens can regulate its production.

Hypotheses: We hypothesize that genetically-determined differences in the androgen action may predispose women to different risks of breast cancer, at least in some groups of women, for examples, women with relatives (mother or sisters) affected by breast cancer.

Methodology: We will use DNA samples and other information collected from women with and without breast cancer in two studies conducted in Northern and Southern California. We will conduct genetic analyses on these DNA samples and later perform statistical analyses to determine whether women with genetically-determined high androgen action may have a lower risk of breast cancer.

Innovative elements: The idea that androgens act directly as a protective factor in breast cancer is still very controversial. Data supporting this idea, although somewhat consistent, are very sparse. There is also a lack of well-conducted studies of the p21 protein in women with and without breast cancer. Our proposed study could provide new clues as to how androgens influence breast cancer risk in women.

Advocacy involvement: Recently, there is a rapidly-growing interest in the use of androgen replacement in symptomatic women undergoing menopause. However recent news reports on the potential hazards of various types of hormone therapy (including androgens) raises great public concern about the possible use of androgens alone or in combination with estrogen and/or progeterone replacement therapy. Therefore it is critical to understand the functions of androgens in the breast, and how these functions might vary in different groups of women. If a direct protective effect of androgens can be demonstrated in some groups of women (such as those with a family history of breast cancer or those on postmenopausal hormone replacement therapy), then androgens might be useful for protecting these women from breast cancer.


Final Report (2006)
Introduction: There has been some laboratory evidence suggesting that androgens may have some protective effect against breast cancer, via binding to androgen receptor. After binding to androgens, androgen receptor mediates their biological functions by modulating the production of the downstream androgen-regulated molecules. However, our knowledge on these androgen-regulated genes is limited and more studies need to be done to help us understand the mechanism of the protective effects of androgens. In one of our recently published study of women with and without breast cancer, we incorporated a genetic marker of androgen action, the lengths of CAG trinucleotide repeats in the androgen receptor gene, to examine the effect of androgens in breast cancer. Our study found a relationship between an increased breast cancer risk with a presumably weaker androgen action (longer CAG repeats) among women with their mother or sister(s) being affected by breast cancer, supporting the postulated protective effect of androgens. However, our previous study is the very small and only included African-American women. In this study, we propose to confirm our important previous finding in two larger studies of three racial groups (African-Americans, Hispanics, and non-Hispanic Whites). Moreover, we will explore possible mechanisms of the protective effect of androgens by examining one specific protein (p21) which plays a very important role in controlling the growth and division of normal and cancer cells, because androgens can directly regulate the production of this protein.

Topic addressed: Will genetically-determined differences among individual in androgen activity and the production of its regulated molecule, p21, influence the development and progression of breast cancer?

Progress toward specific aims: Many genetic changes in the p21 gene have been identified and reported in genetic variant databases since the grant was approved. We have closely examined these newly reported changes and determined which ones to include in our study, according to the predicted potential importance of these changes. We have examined three genetic variants in the p21 gene in 1724 women (505 African-Americans, 644 Hispanics and 575 non-Hispanic Whites). Laboratory assays have been set up for three other genetic variants in the p21 gene.

Future direction and impact: This will be the first study to systematically examine the impact of potentially important genetic changes in the p21 gene on breast cancer. This will also be the first study to propose a pathway (i.e. the p21 pathway) through which androgens may operate in breast tissue, which is done by examining androgen receptor and p21 together. We will continue to finish laboratory measurements on the androgen receptor and the p21 genes and finish analyzing data we collect from the laboratory and from the questionnaire. We hope, by finishing this study, we can provide support to our previous finding of protective effect of androgens on at least some subgroups of women. We also hope we can provide new evidence as to how androgen influences breast cancer development in these women.