IGF1, IGFBP1, and IGFBP3 genes and mammographic density: The Multiethnic Cohort

Abstract

Insulin-like growth factor-I (IGF-I) has mitogenic properties and stimulates cell growth. In this analysis, we investigated the relation between common genetic variation in IGF1, IGFBP1, and IGFBP3, and mammographic density among 819 women of Hawaiian, European, and Japanese ancestry from the Multiethnic Cohort Study. Mammographic density was assessed using a quantitative computer-assisted method. Previously identified tag single nucleotide polymorphisms (SNPs) for IGF1 (26 tag SNPs) and IGFBP1/IGFBP3 (22 tag SNPs) were genotyped among the 819 women. Mixed models were conducted to evaluate the associations between genetic variation and mammographic density. Two SNPs were borderline statistical significantly associated with mammographic density: rs35539615 on IGFBP1 (p 5 0.05) and rs2453839 on IGFBP3 (p 5 0.01). Rs35767on IGF1 (p 5 0.03) was also associated with mammographic density, although in opposite direction of what was expected from previous findings with IGF-I levels. The majority of SNPs were, however, not associated with mammographic density. Analyses stratified by ethnicity showed similar results as the overall analyses for IGF1 and IGFBP1. However, for 4 SNPs in the IGFBP3 gene, the minor allele was associated with lower mammographic density in Japanese Americans and higher mammographic density in Caucasians. Given the large number of SNPs tested and the few borderline significant results, we only found weak evidence that genetic variations in IGFBP1 or IGFBP3 may be related to mammographic density. Ethnicity may modify these relations.Insulin-like growth factor-I (IGF-I) promotes proliferation and inhibits apoptosis in both normal breast cells and breast cancer cell lines. The bioavailability of IGF-I is determined by 6 binding proteins. IGFBP-3 is the predominant binding protein and has been described to also directly affect breast cancer risk in an IGF-I independent manner. 1 In several epidemiologic studies, circulating IGF-I levels were associated with higher breast cancer risk among pre-but not post-menopausal women.2-4 However, more recent results from the EPIC study and the Nurses Health Study (NHS)-II did not show an association between IGF-I levels and breast cancer risk among younger women. 5,6The amount of stromal and glandular tissues of the breast relative to the surrounding fatty tissue can be estimated using mammographic images.7 A high percentage of radiologically dense tissues (percent density) is a strong breast cancer risk factor and is, therefore, often used in etiologic studies as biomarker for breast cancer risk. 8 Circulating levels of IGF-I have been found to be related to mammographic density in premenopausal women in past epidemiological studies, [9][10][11] although this was not confirmed in recent reports. 12,13 In postmenopausal women, this relation does not seem to exist.

Variation in Inflammatory Cytokine/Growth-Factor Genes and Mammographic Density in Premenopausal Women Aged 50–55

“…In the study by Tamimi et al, rs4619 in IGFBP1/IGFBP3 region was positively associated with increased MD in a mixed population of premenopausal and postmenopausal women [27], however, this association was not observed in another study [30] nor in our study. Results from the Multiethnic Cohort study showed no association between IGFBP1/IGFBP3 rs10228265, rs1496497 and rs3110697 and MD in the overall analysis, but a significant association was found when the analysis was limited to women with Hawaiian and Japanese descent [30]. In that study, the results were based on data from premenopausal and postmenopausal women pooled together.…”

“…Consistent with our findings, the majority of previous studies investigating IGFBP1 and IGFBP3 SNPs reported a lack of significant association between IGFBP1/IGFBP3 SNPs including rs2854746, rs1553009, rs1065780, rs2132570, rs3110697, rs35539615, rs4619, and rs6670 and MD. These studies include a cross-sectional study among 1,121 of premenopausal and postmenopausal women from the Nurses’ Health Study cohort investigating 13 tagging SNPs [27], a study of 819 pre- and postmenopausal women of Hawaiian, European, and Japanese ancestry from the Multiethnic Cohort study investigating 22 tagging SNPs [30], and a study of 1,916 premenopausal women within the Prospect-EPIC cohort investigating 11 tagging SNPs [47]. In the study by Tamimi et al, rs4619 in IGFBP1/IGFBP3 region was positively associated with increased MD in a mixed population of premenopausal and postmenopausal women [27], however, this association was not observed in another study [30] nor in our study.…”

“…These studies include a cross-sectional study among 1,121 of premenopausal and postmenopausal women from the Nurses’ Health Study cohort investigating 13 tagging SNPs [27], a study of 819 pre- and postmenopausal women of Hawaiian, European, and Japanese ancestry from the Multiethnic Cohort study investigating 22 tagging SNPs [30], and a study of 1,916 premenopausal women within the Prospect-EPIC cohort investigating 11 tagging SNPs [47]. In the study by Tamimi et al, rs4619 in IGFBP1/IGFBP3 region was positively associated with increased MD in a mixed population of premenopausal and postmenopausal women [27], however, this association was not observed in another study [30] nor in our study. Results from the Multiethnic Cohort study showed no association between IGFBP1/IGFBP3 rs10228265, rs1496497 and rs3110697 and MD in the overall analysis, but a significant association was found when the analysis was limited to women with Hawaiian and Japanese descent [30].…”

“…Further, quantitative microscopy using immunoreactive staining has shown higher amounts of IGF-I in dense breasts compared with lower density breasts, especially in women younger than 50 years of age [13]. Genetic variations in IGF and IGF binding proteins have been associated with MD in several studies [7], [27]–[30]. The role of other growth factors and cytokines such as transforming growth factor-beta (TGF-β), interleukins and tumor-necrosis-factor-alpha (TNF-α) with MD has not been well described.…”

Genetic dissection of intermediate phenotypes as a way to discover novel cancer susceptibility alleles

“…A number of candidate gene studies have attempted to identify variants associated with breast density and suggested that IGF1 polymorphisms are associated with the trait [25][26][27]. These breast density associated polymorphisms, however, do not seem to be associated with increased breast cancer risk [28,29]. More recently, a number of groups have examined the association between GWA study-discovered breast cancer loci and breast density, and have failed to detect consistent associations [30][31][32].…”