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Variants of the Adiponectin and Adiponectin Receptor 1 Genes and Breast Cancer Risk

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Variants of the Adiponectin and Adiponectin Receptor 1 Genes and Breast Cancer Risk Research Article Variants of the Adiponectin and Adiponectin Receptor 1 Genes and Breast Cancer Risk Virginia G. Kaklamani,1 Maureen Sadim,1 Alex Hsi,3 Kenneth Offit,4 Carole Oddoux,5 Harry Ostrer,5 Habibul Ahsan,2 Boris Pasche,1 and Christos Mantzoros3 1Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University; 2Department of Health Studies, Medicine and Human Genetics, University of Chicago, Chicago, Illinois; 3Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; 4Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center; and 5Human Genetics Program, Department of Pediatrics, New York University Medical Center, New York, New York Abstract weight loss, as well as decrease in fat consumption, may lead to Breast cancer risk is higher among obese women and women decreased risk for breast cancer (4, 5). There has also been exten- sive research on the association of diabetes mellitus (DM) and the with diabetes. Adiponectin is a protein exclusively secreted by adipose tissue, circulating levels of which have been associ- metabolic syndrome and breast cancer (6). In a recent meta- ated with breast cancer risk. Whether genetic variants within analysis of 20 case control studies, we reported a 20% increased risk the adiponectin pathway are associated with breast cancer for breast cancer in women with DM (7). In the four cohort studies risk is unknown. To explore the association of genetic variants included in the same meta-analysis, breast cancer risk increased by of the adiponectin (ADIPOQ) and adiponectin receptor 1 24% in patients with DM. The mechanism underlying the increased (ADIPOR1) genes with breast cancer risk, we conducted a case risk of breast cancer in obese and/or diabetic subjects has been control study of female patients with breast cancer and proposed to include changes in levels of estrogens (8, 9), insulin healthy female controls from New York City recruited between resistance, insulin-like growth factors (IGF), as well as IGF-binding 1999 and 2004. We genotyped 733 hospital-based breast cancer proteins (10, 11). cases and 839 controls for 10 haplotype-tagging single nucleo- Several proteins produced by adipose tissue have been studied in tide polymorphisms (SNP) of ADIPOQ and ADIPOR1.Two relation to breast cancer risk. There is emerging evidence that one ADIPOQ SNPs (rs2241766 and rs1501299), which have been of these adipokines, adiponectin, is associated with breast cancer risk (6). Adiponectin, a protein secreted by the adipose tissue, has associated with circulating levels of adiponectin, were associated with breast cancer risk [rs1501299*GG: odd ratios been found to be an endogenous insulin sensitizer, the circulating (OR), 1.80; 95% confidence interval (95% CI), 1.14–2.85; levels of which are decreased in obese and diabetic subjects. rs2241766*TG: OR, 0.61; 95% CI, 0.46–0.80]. One ADIPOR1 Moreover, adiponectin has the potential of regulating the secretion SNP (rs7539542), which modulates expression of adiponectin of estrogens, tumor necrosis factor (TNF) (12, 13), and IGF (14). receptor 1 mRNA, was also associated with breast cancer risk Recently, circulating levels of adiponectin have been found to (OR, 0.51; 95% CI, 0.28–0.92). Based on the known function correlate with breast cancer risk (15–17). Because its levels are of rs2241766 and rs1501299, we categorized individuals by inversely correlated with adiposity (13), it has been suggested that adiponectin signaling status and found that, when compared decreased levels of adiponectin may explain the increased risk of with high signalers, intermediate signalers had a 4.16-fold breast cancer in obesity (13, 18). In fact, several groups have shown increase in breast cancer risk (95% CI, 0.49–35.19), and low that after adjustment for body mass index (BMI), women with higher signalers had a 6.56-fold increase in breast cancer risk (95% adiponectin levels had a 65% reduced risk for breast cancer (15, 16, CI, 0.78–54.89; P = 0.001). This is the first report of an 19). Furthermore, the breast cancer cell lines MCF-7, MDB-MB-231, trend and T47D were found to express both adiponectin receptors association between functionally relevant variants of the adi- ponectin pathway and breast cancer risk. The results warrant ADIPOR1/R2 (15, 20), and exposure of T47D cells to adipo- further studies of the adiponectin pathway in breast cancer. nectin significantly inhibited their proliferation (15). Several adiponectin polymorphisms have been shown to affect [Cancer Res 2008;68(9):3178–84] adiponectin levels, and polymorphisms of both the ligand and its type 1 receptor (ADIPOR1) have been associated with risk for insulin Introduction resistance, cardiovascular disease, and DM (21–28). However, to Breast cancer is the most common malignancy in women in date, the association of these polymorphisms with breast cancer developed countries. In 2007, an estimated 178,480 new cases of risk has not been studied. In this study of breast cancer cases and breast cancer were diagnosed in the United States (1). Several controls, we systematically evaluated selected haplotype-tagging studies have shown an association between obesity, weight gain, single nucleotide polymorphisms (SNP) in genes encoding adipo- and breast cancer risk (2, 3). Furthermore, there is evidence that nectin and its type I receptor in relation to breast cancer risk. Materials and Methods Requests for reprints: Boris Pasche, Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Study participants. As part of institutional review board–approved Cancer Center, Feinberg School of Medicine, Northwestern University, 676 North St. protocols, we collected blood samples from 733 consecutive female patients Clair Street, Suite 880 Chicago, IL 60611. Phone: 312-695-0320; Fax: 312-695-0318; admitted to Memorial Sloan-Kettering Cancer with a diagnosis of breast E-mail: [email protected]. I2008 American Association for Cancer Research. cancer. Recruitment of cases occurred in two phases, the first one between doi:10.1158/0008-5472.CAN-08-0533 January 1, 1998 and December 31, 1999, the second one occurred between Cancer Res 2008; 68: (9). May 1, 2008 3178 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 2008 American Association for Cancer Research. The Adiponectin Pathway and Breast Cancer December 1, 2002 and January 31, 2004. All breast cancer cases were his- Table 1. Characteristics of breast cancer cases and tologically confirmed at Memorial Sloan-Kettering Cancer Center. Infor- controls mation regarding sex, age, age at breast cancer diagnosis, and ethnic status was recorded. In a subset of 152 patients, information on estrogen receptor n n (ER) and progesterone receptor (PR) status as assessed by immunohisto- Cases, (%) Controls, (%) chemistry was collected at the time of case collection. A sample of 839 healthy female volunteers from New York City ages 20 to 87 years was recruited Age (y) between January 1, 2003 and December 31, 2004. The last date of follow-up 20–40 114 (16.2) 27 (7.9) is September 30, 2006. None of the controls had any personal history of cancer 41–50 186 (26.4) 80 (23.5) at the time of blood donation. This was ascertained by a questionnaire 51–60 185 (26.3) 117 (34.3) completed by each healthy volunteer. The controls were matched to cases 61–70 130 (18.5) 73 (21.4) on gender and geographic region and, thus, are representative of the source 71+ 89 (12.6) 44 (12.9) population where the cases come from. Although age categories were obtained Race for all participants, exact age information was not available for some controls. White 563 (76.8) 801 (95.5) However, in that subgroup of individuals, which represents 7.9% of controls, Black 68 (9.3) 19 (2.3) the age ranged from 20 to 40 years (Table 1). None of the controls had any Hispanic 33 (4.5) 10 (1.2) personal history of cancer as ascertained by a questionnaire administered at Asian 22 (3.0) 2 (0.2) the time of enrollment. Ethnic status for cases and controls was self-defined. Unknown 47 (6.4) 7 (0.8) All cases and controls signed an informed consent. All personal identifiers rs266729 from both cases and controls were permanently removed. The study was GG 49 (7) 57 (7.1) approved by the Institutional Review Board. CG 293 (40) 296 (37) DNA isolation. DNA from whole blood lymphocytes was extracted using CC 385 (53) 448 (55.9) the QIAamp DNA Blood Mini kit and was stored at À20jC until use for rs822395 genotyping. All DNA samples underwent whole genome amplification using CC 86 (12) 113 (13.8) the Illustra Genomiphi V2 DNA Amplification kit (GE Healthcare). The AC 314 (43.9) 352 (43) samples were stored at À20jC. AA 316 (44.1) 354 (43.2) Selection of SNPs. Ten haplotype-tagging SNPs were selected for rs822396 genotyping (Table 2). The adiponectin gene has >10 SNPs (22, 27) and two GG 19 (2.7%) 33 (4) linkage disequilibrium blocks with a block boundary between À2,049 and AG 187 (26.1%) 210 (25.6) À450 (Fig. 1A; ref. 24). We selected to genotype rs266729 (5¶ flanking region), AA 510 (71.2) 577 (70.4) rs822396 (intron 1), and rs822395 (intron 1) to tag block 1 and rs1501299 rs2241766 (exon 2) and rs2241766 (intron 2) to tag block 2 (Fig. 1A) as these are the TT 524 (73.6) 520 (64.9) five most common SNPs and have been studied more extensively by others TG 167 (23.5) 252 (31.5) as to their functionality and relation to diseases such as DM (21–24). GG 21 (2.9) 29 (3.6) ADIPOR1 has >28 SNPs and two linkage disequilibrium blocks (Fig.
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