The IGF Pathway & Breast Cancer Risk in African Americans

Institution: University of California, Irvine
Investigator(s): Susan Neuhausen, Ph.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9PB-0142 Award: $422,467
Award Type: Request for Applications
Research Priorities
Etiology and Prevention>Prevention and Risk Reduction: ending the danger of breast cancer



Initial Award Abstract (2003)
Approximately 1 in 8 women in the US develop breast cancer at some point in their lifetime. Although the overall incidence of breast cancer in African Americans is slightly lower than in Caucasians and is the same for women under age 50 years, the age-adjusted mortality rates for women under 50 years is almost double. African American women present with more aggressive breast cancer at diagnosis. Therefore, it is imperative that we identify risk factors for breast cancer in this population. Breast cancer results from complex interactions among genetic, hormonal, and environmental factors. Thus, knowledge of genetic risk factors that contribute to breast cancer risk is crucial to design both preventative and therapeutic strategies and to identify at risk individuals, in order to reduce the incidence of and death from this disease.

Clinically important genetic risk factors that may result in differences in risk for developing breast cancer may involve genes involved in cell growth and multiplication, factors central to cancer development. This proposal will test the hypothesis that common changes in genes in the insulin-like growth factor pathway may be risk factors for breast cancer. We will study these genes in a set of African American women with breast cancer, as these women have been under-studied and often seem to present with a more aggressive breast cancer at a younger age with a higher associated mortality. Therefore, this group of women could especially benefit from identification of risk factors for breast cancer.

We propose to identify genes that are important in breast cancer occurrence and progression through comparing specific genetic changes in DNA from African American women with breast cancer (cases) to African American women of the same age without breast cancer (controls). We will study 600 women with breast cancer and 232 women without. Statistical methods will be used to analyze the data looking at the main effects of the genetic changes as well as their interactions with other genetic changes and with lifestyle factors such as body mass index. We will look at their associations with breast cancer risk, age at which it was diagnosed, and tumor factors such as stage, size of tumor, and involvement of lymph nodes.

To our knowledge, this will be the first comprehensive study to investigate the role of changes in a series of genes involved in the insulin-like growth factor pathway, which may directly affect cell growth. We are examining multiple variants; many in genes that have never previously been examined in this context. Moreover, in previous studies, only one or two variants per gene and only one or two genes in a pathway were examined. We will be using sophisticated new approaches that analyze multiple linked variants in a single gene and that allow evaluation of multiple genes in a single mechanistic pathway. Importantly, we are focusing on African Americans, who are at high risk of aggressive, early onset breast cancer. Few previous studies have been undertaken in this population.


Final Report (2007)
Approximately 1 in 8 women in the US develop breast cancer. Although the overall incidence of breast cancer in African Americans is slightly lower than in Caucasians and is the same for women under age 50 years, the age-adjusted mortality rates for women under 50 years is almost double. African American women present with more aggressive breast cancer at diagnosis. Therefore, it is imperative that we identify risk factors for breast cancer in this population. Breast cancer results from complex interactions among genetic, hormonal, and environmental factors. Thus, knowledge of genetic risk factors that contribute to breast cancer risk is crucial to design both preventative and therapeutic strategies and to identify at risk individuals, in order to reduce the incidence of and death from this disease.

This proposal tested the hypothesis that common changes in genes in the insulin-like growth factor pathway may be risk factors for breast cancer. We examined multiple variants; many in genes that have never previously been examined in this context. Moreover, in previous studies, only one or two variants per gene and only one or two genes in a pathway were examined.

The specific aims of our study were:
  1. to screen Single Nucleotide Polymorphisms (SNPs) in genes involved in the IGF signaling pathway;

  2. to genotype SNPS selected in Aim 1 in entire study sample; and Aim 3) to evaluate the association of SNPs in genes in the IGF pathway with risk of breast cancer.

We found significant associations of haplotypes in IGFBP1, IGFBP2, and IGFBP5 and risk of breast cancer. (A haplotype is a set of closely linked alleles (genes or DNA polymorphisms) inherited as a unit.) We then attempted to validate these significant associations in a case-control set of Nigerian women. We were able to replicate the significant associations seen in IGFBP2 and IGFBP5. Based on those initial findings, we genotyped a total of 34 single nucleotide polymorphisms (SNPs) across the region in both study populations. Statistically significant associations with breast cancer were observed with p-values as low as p=0.0038 and p=0.01 in African Americans and Nigerians, respectively. This study is the first to report associations between genetic variants in IGFBP2 and IGFBP5 and breast cancer risk.

These results provide evidence that genetic variation in the IGF signaling pathway plays a role in risk of breast cancer. The finding of a significant association in two independent populations of African descent, the consistent localization in the two populations, and the biological plausibility of the association between the candidate genes and the phenotype provide strong evidence for association with this locus. Further replication in larger populations of African descent, as well as in non-African populations, are required to increase confidence in the reported association and to localize the etiological component of the association. Our hope is that by identifying genes in the IGF pathway that are associated with breast cancer risk and progression of the disease, we will provide clues for the development of better therapeutic strategies for disease prevention and treatment.


Symposium Abstract (2005)
Breast cancer results from complex interactions among genetic, hormonal, and environmental factors. Approximately 1 in 8 women in the US will develop breast cancer at some point in their lives. Although the incidence of breast cancer is similar among African Americans and Caucasians, African-American women have more aggressive breast cancer at diagnosis and their age-adjusted mortality rates for women under 50 years is almost double that of Caucasians. Therefore, it is imperative that we identify risk factors for breast cancer, particularly in this population.

This proposal tests the hypothesis that common changes in genes in the insulin-like growth factor (IGF) pathway may be risk factors for breast cancer. We are using powerful new approaches that combine multiple linked genetic changes (variants) in a single gene to form haplotypes and allow for evaluation of multiple genes in this mechanistic pathway. A haplotype is the set of genetic markers on the same chromosome that are inherited together.

We first identified variants in genes in the IGF pathway. We have performed genotyping for IRS1 G972R, SHC M200V, PI3K -359A>C, and multiple variants in the IGFBP1, IGFBP2, IGF1, and IGF1R genes in 321 African-American breast cancer cases and 269 unaffected controls. We have completed preliminary analyses of the effects of the individual variants and their associations with development of breast cancer and histological stage and grade of the disease. For IRS1 G972R, we found significant associations with age at diagnosis (p = 0.004) and with tumor grade (p = 0.015). We observed significant associations with risk of breast cancer with 1.4-fold increased risks for an IGF1R variant and multiple IGF1 variants, and 2-fold increased risks for several IGFBP2 variants. During the next year, we will be performing more complex analyses, including investigating the role of haplotypes in each gene, and exploring interactions among genes and between genes and lifestyle factors (e.g., weight, physical activity). Because these genes are in the same pathway, an analysis including multiple genes may provide improved risk estimates as compared to examining genes singly. Higher serum levels of IGF1 have been associated with increased breast cancer risk, so the genetic changes we identified in IGF1 may reflect serum level changes.

Our hope is that by identifying changes in genes in the IGF pathway that are associated with breast cancer risk and progression of the disease, we will provide clues for the development of better therapeutic strategies for disease prevention and treatment. As an example for prevention, diet affects serum levels of IGF1, suggesting that a woman at high risk for breast cancer could modify her diet to reduce IGF1 levels. It should be possible to target African-American women who are at high risk of developing aggressive cancer for prevention strategies. These genetic changes will likely be important for women of all races and ethnicities. This knowledge is crucial in order to reduce the incidence of and death from this disease.