Vitamin D & Genetics of Vitamin D Receptor in Breast Cancer

Institution: University of Southern California
Investigator(s): Sue Ann Ingles, DrPH -
Award Cycle: 1995 (Cycle I) Grant #: 1IB-0353 Award: $80,976
Award Type: IDEA
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle

Initial Award Abstract (1995)
The specific aims of this proposal address the BCRP priority issues of the underlying biological causes of breast cancer (etiology) and the development of the disease (pathogenesis): we plan to test whether genetic variants in the vitamin D receptor (VDR) are related to breast cancer incidence and whether blood vitamin D levels interact with the genetically determined VDR variants to influence the risk of breast cancer. These genetic variants have recently been shown to have a strong effect on bone density; and, since vitamin D plays an important role in cellular growth and differentiation (the process by human body cells become different and specific, e.g., a kidney or breast cell), it is possible that variation in the VDR may affect breast cancer in a similar manner.

To investigate this hypothesis, we propose to conduct a case control study of 200 matched pairs of breast cancer cases and controls (that is, similar women who do not have breast cancer), equally divided among four ethnic groups: African-American, Hispanic, Japanese, and White. DNA from cases and controls will be typed (examined) for the commonly used marker (BSMI) which is tightly linked to the suspected VDR causal mutation. We will also type one of the variants which is a candidate for the causal mutation. Since inconsistencies among previous studies suggest that different BSMI variants may be associated with the causal mutation in different ethnic populations, we will examine linkage disequilibrium between the two loci in each of the four ethnic groups. These data will provide information about the usefulness of BSMI as a measure for the VDR causal mutation.

Given the role that vitamin D is known to play in cellular growth and differentiation, the recent work using vitamin D analogues to suppress the growth of breast cancer cells, and the recent discovery of VDR variants which appear to account for a large proportion of genetic variation in bone density, we feel that there is sufficient evidence to investigate the role of the VDR in breast cancer incidence. A positive result would have implications for breast cancer prevention and treatment: administration of vitamin D or its analogues might be useful for prevention of breast cancer or its progression in individuals with high risk variants. Since the suspected high-risk variant is common in the population, a positive result could have a large impact on reducing the incidence of breast cancer in California.

Final Report (1996)
The aims of this project were to determine whether there are genetic variants of the vitamin D receptor (VDR) which increase risk of breast cancer and, if high-risk variants are found, to determine whether higher levels of vitamin D in the blood are protective against breast cancer in women who carry the high-risk form of VDR.

We have identified high-risk variants in not one, but two areas of the VDR gene. Preliminary results indicate that women with one or both of these high-risk variants may have a 3-10 fold increased risk of breast cancer compared to women with two low risk variants. These results were obtained by studying African-American women. Testing Hispanic, white, and Japanese-American women is still in progress. Measurement of plasma vitamin D levels is also in progress, and will be used to determine whether high levels of vitamin D in the blood can protect against breast cancer in women who carry a high-risk form of the VDR gene.

The high-risk variants that were identified are relatively common, thus if we are able to modify the effects of these high risk genetic variants (e.g. by improving nutrition or by giving synthetic vitamin D), we may be able to prevent a large number of breast cancers.

Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies.
Periodical:Cancer Epidemiology Biomarkers and Prevention
Index Medicus: Cancer Epidemiol Biomarkers Prev
Authors: Ingles SA, Haile RW, Henderson BE, Kolonel LN, Nakaichi G, Shi CY, YMC, Ross RK, Coetzee G
Yr: 1997 Vol: 6 Nbr: 2 Abs: Pg:93-8