HER-2/neu Gene Variations and Breast Cancer Risk

Institution: University of Southern California
Investigator(s): Michael Press, M.D., Ph.D. -
Award Cycle: 2001 (Cycle VII) Grant #: 7PB-0051S Award: $1,182,463
Award Type: Request for Applications
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle
Community Impact of Breast Cancer>Disparities: eliminating the unequal burden of breast cancer

Initial Award Abstract (2001)
There are important differences between breast cancers in African Americans and Whites. After taking tumor size, disease spread, and hormone-receptor status into consideration race remains as a factor effecting breast cancer survival. Our proposal is focused on understanding an important breast cancer-related gene (HER-2/neu) in normal cells from women with and without breast cancer. Approximately 25% of breast cancers duplicate the HER-2/neu gene repeatedly so they have multiple copies. This is referred to as HER-2/neu gene amplification. HER-2/neu gene amplification is associated with aggressive breast cancers and a shorter overall survival. By understanding the role of variants of the HER-2/neu gene in patients and healthy women we expect to gain understanding both of the role of this gene in breast cancer causation and in breast cancer prevention.

While genes known to cause breast cancer, such as BRCA1 and BRCA2, are clearly important, few women have mutations in these genes. There is an emerging, possibly larger, role for "normal" gene variations, referred to as polymorphisms, which are wide-spread in the population but have weaker effects on the disease process. Racial differences in breast cancer may possibly be related to differences in the frequency of various "normal" genes (polymorphism) in these populations.

The HER-2/neu gene is one which can be present in either of two "normal" forms. One of these "normal" forms (a polymorphism) has been found to be associated with a higher risk of breast cancer in Chinese women. The role of this polymorphism in African American and white women has not been determined.

We plan to investigate two "normal" forms of the HER-2/neu gene in a large number of African American and white women in Los Angeles County who participated in an epidemiologic case-control study. We will determine:

1. How frequent is the HER-2/neu polymorphism in African American and white women without breast cancer (control subjects)?

2. How frequent is the HER-2/neu polymorphism in African American and white women with breast cancer (cases)?

3. Does breast cancer risk vary according to whether a woman inherits the HER-2/neu olymorphism?

4. Is breast cancer risk higher or lower among women with the HER-2/neu polymorphism who have other exposures like early menses, late menopause, fewer or no pregnancies, never breast fed, used birth control pills, or hormone replacement therapy, or do not exercise?

5. Does inherited HER-2/neu polymorphism status effect which breast cancers have gene amplification?

The study will analyze blood cells from African American and white women with breast cancer (cases) and women without breast cancer (controls). The blood cell DNA will be characterized for an inherited "normal" polymorphism in the HER-2/neu gene. Breast cancer tissue will be analyzed for the acquired HER-2/neu gene change, HER-2/neu gene amplification. Information previously collected from these women will be compared with the laboratory results to determine if there are associations between various environmental exposures (especially hormonal exposure) and breast cancer risk.

This research should answer some new questions about breast cancer causation in African American and white women for a gene which known to play an important role in the disease process, in overall survival and in selection of breast cancer treatment. In addition, understanding the interaction of inherited HER-2/neu polymorphisms with breast cancer risk factors could be important in the prevention of breast cancer.

Final Report (2006)
The HER-2/neu gene is a member of the epidermal growth factor receptor family of genes that code for membrane receptor proteins. HER-2/neu is an important gene in breast cancer with acquisition of HER-2/neu gene amplification associated with poor patient prognosis. HER-2/neu gene amplification is also a predictive marker of responsiveness to selected forms of therapy. The goal of the current project is to evaluate the potential for increased breast cancer risk associated with an inherited single nucleotide polymorphism in Codon 655 (a codon is that part of DNA or RNA that codes for a single amino acid) in the transmembrane domain of this receptor gene. In order to accomplish this goal we are evaluating this single nucleotide polymorphism in blood samples from 973 women with breast cancer and approximately 904 matched control women.

To date we have collected the blood samples from 1582 women, -983 cases and -599 controls. The HER-2/neu single nucleotide polymorphism (SNP) has been analyzed in 1414 women. We compared four different methods (TagMan, 1414 samples; restriction fragment length polymorphism (RFLP), 367 samples; DNA chip technology, 40 samples; and DNA sequencing, 40 samples) for assessment of this SNP to confirm the accuracy of these methods.

We found complete agreement among these methods and have selected a single method to process all future samples. The SNP results for the analyzed samples overall can be summarized as follows:

HER-2/neu Single Nucleotide Pol morphism at Codon 655
Codon 655 Genotype: 

Supplement Award Abstract (2003)
The California Breast Cancer Research Program presented a Diversity Supplement for Dorothy Hong, a student in Dr. Press' lab.

Mentor's Summary:
Mentoring activities.
Dorothy Hong and I have met on a regular basis to discuss her research in my laboratory and her progress in the Medical School curriculum. Dorothy has participated in research projects in my laboratory, funded by the California Breast Cancer Research Program ("HER-2/neu Gene Variations and Breast Cancer Risk"). She has made good progress in the laboratory and has presented her work at two different local scientific meetings and one state-wide scientific meeting. In addition, she is excelling in her Medical School courses.

Discuss barriers and facilitators to mentoring trainee.
There have been no barriers to mentoring Dorothy. She is diligent, hard-working, cooperative, very smart and a delightful person. I thoroughly enjoy working with her.

Trainee's Summary
List all completed activities from the training plan in your supplement application.
1) I was involved in conducting research during the summer semester of 2002 in the laboratory of Dr. Michael F. Press. The project supported by the California Breast Cancer Research Program, was "HER-2/neu Gene Variations and Breast Cancer Risk."
2) I continued to work part-time in the laboratory during the academic year collecting more data.
3) In addition to laboratory work and my attendance in the regular medical school curriculum, I attended weekly Breast Cancer Program conferences and Cancer Center Grand Rounds.

Describe facilitators and barriers to completing activities in training plan.
There were no barriers to completing any activities in the training plan. Dr. Press has always been a dedicated mentor and I have a lot of support from him. Because of this project I had the opportunity to present my work at the Western Regional Meeting in February 2003. It was a very interesting experience because I could communicate with medical students and scientists at the meeting about what I had done and received very positive feedback from them.

Describe any additional mentoring activities not identified in training plan.
Dr. Press has given me timely feedbacks and formal written evaluations about my performance in his laboratory.

Describe any outcomes that are the result of this mentoring opportunity (e.g. inclusion on a published paper, admittance into a program of further study, opportunities for further training in breast cancer research).
During the spring semester, I submitted an abstract to the Western Regional Meeting and was invited to give a fifteen-minute platform presentation in Carmel, California. I also participated in the 2003 Medical Student Research Forum and Poster Day held in the Keck School of Medicine.

Describe the impact this mentoring opportunity has had on your future career goals. Will you continue to work in breast cancer research?
I will definitely continue to work in breast cancer research, especially after attending meetings and being exposed to other research topics. My future career goal is still to become a physician scientist who will conduct breast cancer research and take care of breast cancer patients based on scientific evidence. This mentoring opportunity helps to solidify my goal.