Progress made in understanding breast cancer risk

(Press-News.org) ORLANDO, Fla. — August 3, 2011 — A woman's ethnicity as well as her genetic makeup are two of the main risk factors for hereditary breast cancer. Research into understanding and treating hereditary breast cancer will be presented today at the Era of Hope conference, a scientific meeting hosted by the Department of Defense Breast Cancer Research Program (BCRP).

About 5 to 10 percent of breast cancers are thought to be hereditary, resulting from defective genes inherited from a parent. The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 gene; the risk may be as high as 85 percent for members of some families with these mutations.1 And while White women are more likely to develop breast cancer, African American women are more likely to die from the disease, partly because African Americans have more aggressive tumors. Studies presented at Era of Hope explore the genes that contribute to breast cancer risk in African Americans, and the possibility that vitamin D intake might help mitigate it in this population. Other studies look at how daughters of women with BRCA 1 or BRCA2 mutations manage their own risk of breast cancer, and how the identification of a particular gene might lead to treatment for the very deadly triple-negative breast cancer.

"Some women are born with a greater risk of developing more aggressive forms of breast cancer," said Captain Melissa Kaime, M.D., Director of the Congressionally Directed Medical Research Programs (CDMRP), under which the BCRP is managed. "Research presented at the Era of Hope provides new insights into the specific gene mutations that lead to this risk, enabling us to develop targeted treatments and to better assist those women to manage their inherited predisposition to the disease."

Toward Understanding Genetic Susceptibility for Breast Cancer in Women of African Ancestry
Principal Investigator: Christopher Haiman, ScD, University of Southern California

Studies of genetic links to breast cancer have been conducted almost exclusively in populations of European ancestry and have firmly established a number of gene locations that are associated with breast cancer susceptibility. While these discoveries provide support for the theory that many genes can predispose someone to cancer,2 and provide clues to important biological pathways involved in the development of cancer, the degree to which these genetic associations can be generalized broadly to other racial/ethnic populations is unclear. A genome-wide association study among women of African ancestry was initiated to identify additional genetic risk factors for breast cancer in this population.

As a first step, this study examined genetic variation at all 18 genetic regions previously associated with breast cancer risk to both improve the current set of risk markers in African Americans and to identify new variants that may be associated with risk. Through fine-mapping, markers were identified that better define the association in African Americans in seven regions. Among them, three showed evidence of independent signals. All together, these risk markers allow for an improved ability to predict the risk of breast cancer development for African Americans over previously-reported markers.

"We are encouraged by these findings, as we continue to learn more about genetic susceptibility to breast cancer in African American women," said Dr. Christopher Haiman of the University of Southern California. "We look forward further research aimed at identifying risk variants for breast cancer in this population, in particular those for estrogen receptor negative disease which has a greater incidence among women of African ancestry. We are also working to further develop and validate this risk model to improve breast cancer risk prediction in this population using risk variants."

What Do Young Adult Daughters of BRCA Mutation Carriers Know About Hereditary Risk and How Much Do They Worry
Principal Investigator: Andrea Farkas Patenaude, PhD, Dana-Farber Cancer Institute

Women with BRCA1 or BRCA2 gene mutations have a 50 percent chance of passing the mutation and its associated high risks for breast and ovarian cancer along to their daughters. Mutations in either of these genes increase the risk of breast cancer by 85 percent (which often occurs at unusually young ages), and ovarian cancer risk by up to 60 percent.3 The ability of daughters of mothers who are BRCA1 or BRCA2 mutation carriers to make informed health decisions is dependent on them becoming knowledgeable about their risks, genetic testing and options for screening and risk-reducing surgery. This study uncovers the genetic knowledge, attitudes, health behaviors and life plans of daughters, ages 18-24 years, of mothers who are BRCA1 or BRCA2 mutation carriers. Data from the study will define specific health educational, psychological, insurance and medical needs of this population.

Written questionnaires and telephone interviews revealed that the young women in this study lacked knowledge about hereditary breast or ovarian cancer genetics when compared with women who had undergone genetic counseling. Further, the young women exhibited a limited understanding of screening and risk-reduction options and of the recommended age for initiating screening. Worry about hereditary breast or ovarian cancer was high among daughters, with about a third scoring above cut-offs on the Impact of Event Scale, 4 which measured their distress related to knowledge of hereditary cancer. In addition, 40 percent of the young women reported that they worried a great deal or to an extreme about hereditary cancer.

"Young, high-risk women have little knowledge about the probabilities and options for managing the cancers for which their risks are remarkably increased. Further, many report intense anxiety related to their potential cancer development," said Dr. Andrea Farkas Patenaude of the Dana Farber Cancer Institute. "These data support the need and can provide the foundation for the development of targeted educational materials to reduce that anxiety and ultimately improve participation in effective screening and risk-reducing interventions that can improve survival and quality of life for these young women."

Vitamin D and Breast Cancer in African American and European American Women
Principal Investigator: Song Yao, PhD, Roswell Park Cancer Institute, Buffalo

Low levels of vitamin D are thought to be linked to increased risk of breast cancer, particularly the triple-negative (TN) subtype. With TN breast cancer, cells test negative for estrogen receptors (ER-), progesterone receptors (PR-), and the HER2 (HER2-) gene, making the cancer unresponsive to the currently available hormonal or HER2 targeted treatments. 5 African American (AA) women typically have significantly lower levels of vitamin D than their European American (EA) counterparts, potentially accounting for the strikingly high incidence of TN breast cancer among this group. This study observed the associations between the level of vitamin D and the TN status of the patients, and also examined single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene. SNPs are genetic variations in a single DNA molecule that can have a major impact on risk of diseases and response to treatments. 6

Women with breast cancer showed lower levels of vitamin D than women without cancer (22.8 versus 26.2 ng/mL), and those with TN breast cancer before menopause had the lowest levels (17.5 ng/mL). For each 10 ng/mL increase in vitamin D, there was a 64 percent reduction in the risk of having TN breast cancer. The prevalence of severe vitamin D deficiency (< 10 ng/mL) was almost six times higher in African American women than that in European American women (34.3 percent vs 5.9 percent). Two SNPs were found to explain, in part, the higher risk of ER-negative breast cancer in AA women.

"Our results indicate that blood levels of vitamin D are inversely linked with the risk of breast cancer, particularly TN type, which is more common in African American women and is known to have poorer prognosis." said Dr. Song Yao of Roswell Park Cancer Institute. "To our knowledge, this is the first study to indicate that vitamin D and related genetic variants may account, in part, for breast cancer racial disparities. Future work is warranted to investigate whether these disparities can be mitigated, to some extent, by maintaining sufficient levels of vitamin D."

This work was also supported by a Breast Cancer Research Foundation award to Dr. Christine Ambrosone, co-investigator on this project.

Identification of Genes Required to Suppress Tumor Transformation in Triple Negative Breast Cancer
Principal Investigator: Stephen Elledge, PhD, Brigham and Women's Hospital Subtypes of breast cancer are generally diagnosed based on the presence or absence of three receptors that play important roles in breast cancer — estrogen receptors, progesterone receptors, and human epidermal growth factor receptors. The triple-negative (TN) subtype is characterized by the absence of all three of these receptors and does not respond to current targeted breast cancer therapies. African American women are at a greater risk of developing TN breast cancer than less aggressive subtypes of breast cancer. Dr. Stephen Elledge and colleagues recently identified a gene, PTPN12 tyrosine phosphatase, as a tumor suppressor in women with TN breast cancer. PTPN12 suppresses the growth and transformation of mammary epithelial cells in breast tissue, and is frequently compromised in TN breast cancer. Restoring PTPN12 function in deficient TN breast cancer cells can block their ability to form tumors and become metastatic. This effect is also seen in cells with inhibition of PTPN12-regulated tyrosine kinases thus suggesting that TN breast cancer cells are dependent on proto-oncogenic tyrosine kinases constrained by PTPN12. "Our data suggests that PTPN12 is commonly inactivated in triple-negative breast cancer and results in activation of cellular tyrosine kinases which could be targets for this intractable cancer," said Dr. Elledge. "While we are still understanding the triple-negative subtype, our research findings could play a key role in improving the treatment of this disease." ### About the Era of Hope The Era of Hope (EOH) conference joins scientists, clinicians and breast cancer advocates committed to advancing research on the prevention, detection, diagnosis and treatment of breast cancer. From August 2-5, 2011 in Orlando, Florida, the EOH will feature prominent scientists and clinicians with presentations of recent remarkable advances in breast cancer research funded by the Department of Defense Breast Cancer Research Program (BCRP). This research challenges paradigms and pushes boundaries to identify innovative, high-impact approaches for future breast cancer research and discoveries. The EOH conference is recognized as one of the premier breast cancer research conferences, and this year marks the sixth conference of its kind. The EOH will bring together more than 1,600 BCRP awardees, advocates, and invited speakers in an atmosphere of collaborative thinking in the fight against breast cancer. The EOH is a unique opportunity for advocates and expert scientists from different fields and research areas to discuss unanswered questions, share ideas, identify promising directions in breast cancer research, and develop collaborative partnerships. The conference will unveil innovative research and discoveries that are essential to ultimately eradicating the disease. For more information about the EOH, please visit https://cdmrpcures.org/ocs/index.php/eoh/eoh2011 Follow the Era of Hope conference on Twitter @EraofHope.

About the Congressionally Directed Medical Research Programs In the early 1990s, the breast cancer advocacy community launched a grassroots effort to raise public awareness for the crucial need of increased funding in breast cancer research. Beginning in fiscal year 1992 (FY92), Congress appropriated $25 million for breast cancer research to be managed by the Department of Defense. The following year, Congress continued to respond to the advocacy movement and appropriated $210 million for breast cancer research, marking the beginning of the Congressionally Directed Medical Research Programs (CDMRP). The CDMRP represents a unique partnership among the public, Congress, and the military. Because of continued and expanded advocacy efforts, the CDMRP has grown to encompass multiple targeted programs spanning cancer research, military medical research, and other disease, injury, or condition specific research. The CDMRP has received $6.525 billion in appropriations from its inception through FY11 and more than 10,000 awards have been made across 25 different programs through FY10. For more information about the CDMRP, please visit http://www.cdmrp.army.mil.

1 Botkin JR, Smith KR, Croyle RT, et al. Genetic testing for a BRCA1 mutation: prophylactic surgery and screening behavior in women 2 years post testing. Am J Med Genet A. 2003 Apr 30; 118A(3):201-9.

2 http://www.nature.com/ng/journal/v31/n1/full/ng853.html 3 Botkin JR, Smith KR, Croyle RT, et al. Genetic testing for a BRCA1 mutation: prophylactic surgery and screening behavior in women 2 years post testing. Am J Med Genet A. 2003 Apr 30; 118A(3):201-9.

4 Horowitz MJ, Wilner NR & Alvarez W (1979). Impact of Event Scale: A measure of subjective stress. Psychosomatic Medicine 41, 209- 218. 5 http://www.breastcancer.org/symptoms/diagnosis/trip_neg/ 6 http://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtml#snps