Published OnlineFirst May 21, 2013; DOI: 10.1158/1055-9965.EPI-13-0258 Cancer Epidemiology, Research Article Biomarkers & Prevention Circulating Adipokine Levels and Endometrial Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Patricia Luhn1,2, Cher M. Dallal1,2, Jocelyn M. Weiss3, Amanda Black1, Wen-Yi Huang1, James V. Lacey, Jr.5, Richard B. Hayes4, Frank Z. Stanczyk6, Nicolas Wentzensen1, and Louise A. Brinton1 Abstract Background: Circulating adipokine levels may be associated with endometrial cancer risk, yet few studies have evaluated these markers prospectively. Methods: We conducted a nested case–control study of postmenopausal women in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n ¼ 78,216), including 167 incident endometrial cancer cases and 327 controls that were matched on age, study center, race, study year of diagnosis, year of blood draw, time of day of blood draw, and menopausal hormone therapy (MHT) use. Adipokine and estradiol levels were categorized into tertiles (T). ORs and 95% confidence intervals (CIs) for the associations of adiponectin, leptin, and visfatin with endometrial cancer risk were estimated by conditional logistic regression, adjusting for known endometrial cancer risk factors, including body mass index (BMI) and circulating estradiol levels. ¼ Results: Adiponectin levels were inversely associated with risk of endometrial cancer [ORT3vsT1 0.48; 95% P < P CI, 0.29–0.80); trend 0.01], whereas elevated leptin levels showed a positive association [2.77 (1.60–4.79); trend < 0.01]. These results remained significant after adjustment for estradiol, but not after further adjustment for BMI. When analyses were restricted to non-MHT users, associations of adiponectin and leptin were P ¼ stronger and remained significant after adjustment for estradiol and BMI [0.25 (0.08–0.75); trend 0.01 and P ¼ 4.72 (1.15–19.38); trend 0.02, respectively]. Nonsignificant positive associations were observed for visfatin. Conclusion: Adipokines may influence endometrial cancer risk through pathways other than estrogen- mediated cell growth in postmenopausal women not currently on MHT. Impact: Understanding how adipokines influence endometrial cancer risk may help to elucidate biological mechanisms important for the observed obesity–endometrial cancer association. Cancer Epidemiol Biomarkers Prev; 22(7); 1304–12. Ó2013 AACR. Introduction hypotheses about the mechanism by which obesity Adipose tissue produces and secretes many metaboli- increases risk in postmenopausal women have largely cally active molecules, including adipokines such as adi- centered around the aromatization of androgens in adi- ponectin, leptin, and visfatin (1). Although obesity is a pose tissue leading to increased circulating estradiol well-known risk factor for endometrial cancer, the rela- levels (2). Other mechanisms via inflammation, insulin tionship between these obesity-related factors and endo- resistance, and adipokines, however, are thought to be metrial cancer risk remains largely unclear. To date, important. Adiponectin, the most abundant adipokine, has been suggested to have anti-angiogenic, anti-inflammatory, Authors' Affiliations: 1Division of Cancer Epidemiology and Genetics; and anti-apoptotic properties (3–5). In addition, increased 2Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland; 3Mount Sinai Adolescent adiponectin levels in serum have been shown to reduce Health Center; 4Department of Population Health, NYU Langone Medical blood glucose and insulin levels and thus are inversely Center, New York, New York; 5Beckman Research Institute of City of Hope, correlated with obesity and type-2 diabetes (6, 7). Results Duarte; and 6Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, California from the limited number of epidemiologic studies eval- uating circulating adiponectin levels and endometrial Note: Supplementary data for this article are available at Cancer Epide- miology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/). cancer are inconsistent. Case–control studies have reported an inverse association; however, these studies Corresponding Author: Patricia Luhn, Division of Cancer Epidemiology and Genetics, Hormonal and Reproductive Epidemiology Branch, National used postdiagnostic serum and thus could not address Cancer Institute, 6120 Executive Blvd, Suite 550, Rockville, MD 20892. temporality (8–11). To date, only 3 prospective studies Phone: 301-451-5033; Fax: 301-402-0916; E-mail: [email protected] have been conducted; 1 study reported an inverse asso- doi: 10.1158/1055-9965.EPI-13-0258 ciation with prediagnostic serum levels (12), whereas the Ó2013 American Association for Cancer Research. other 2 reported no association (13, 14). 1304 Cancer Epidemiol Biomarkers Prev; 22(7) July 2013 Downloaded from cebp.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst May 21, 2013; DOI: 10.1158/1055-9965.EPI-13-0258 Adipokines and Endometrial Cancer Risk Leptin has contrasting biological functions to adipo- the endometrium between their initial screening visit and nectin; it has been shown to promote cell proliferation, April 1, 2006. Controls had to be alive at the time of the angiogenesis, and metastasis in certain cell lines (1, 5, 15). diagnosis of the case and were matched 2:1 on age (5-year Serum leptin levels are positively correlated with obesity intervals), study center, race (white/black/other), indi- and function to regulate appetite, weight, metabolism, vidual study year of diagnosis, individual year of blood and fertility (16, 17). Results from case–control studies draw, time of day of blood collection (AM/PM), and (8, 18, 19) that suggested a positive association between menopausal hormone therapy (MHT) use at baseline leptin levels and endometrial cancer have recently been (never/former/current/unknown). Subjects with miss- corroborated in a prospective study (13). Few studies ing information on BMI, diabetes, and smoking informa- of adipokines and endometrial cancer risk have included tion (n ¼ 2 for cases and n ¼ 4 controls), 1 case with measures of both adiponectin and leptin (8, 10, 13) and insufficient serum volume for assays and 1 case whose only 2 have reported associations for their ratio (8, 13). serum sample was later determined to have been drawn The leptin:adiponectin ratio has been suggested to be a after cancer diagnosis were excluded from analyses. The surrogate marker of insulin resistance in both diabetic final study population consisted of 167 cases and 327 and nondiabetic women (20, 21) and has been shown to matched controls; there were 7 cases with 1 matched be positively associated with breast and colorectal cancer control after applying exclusion criteria. (22, 23). Visfatin, also known as nicotinamide phosphoribosyl- Laboratory assays transferase (Nampt) or pre–B-cell colony-enhancing Serum concentrations of adiponectin, leptin, visfatin, factor, is an adipokine that was recently discovered in and estradiol were measured in the Reproductive Endo- visceral fat. It has been implicated in a variety of metabolic crine Research Laboratory of Dr. Frank Stanczyk (Univer- and stress functions as well as cellular energy metabolism sity of Southern California, Los Angeles, CA). Leptin and (24–26). Recent epidemiologic studies have shown direct adiponectin were measured by radioimmunoassay (RIA) associations of serum visfatin levels with gastric carcino- using reagents obtained from Millipore Linco Research ma, colorectal adenocarcinoma, and postmenopausal (St. Charles, MO). The leptin assay sensitivity is 0.5 breast cancer (27–29). In addition, a few studies have ng/mL, and the interassay coefficients of variation (CV) suggested a link between visfatin and polycystic ovary are 6.2%, 4.7%, and 3.6% at 4.9, 10.4, and 25.6 ng/mL, syndrome, a risk factor for endometrial cancer (30–32); respectively. The adiponectin assay sensitivity is 1.0 however, to date, the association of visfatin with endo- ng/mL, and the interassay CVs are 9.2%, 6.9%, and metrial cancer risk has not been evaluated. 9.2% at 1.5, 3.0, and 7.5 ng/mL, respectively. Visfatin was To shed further light on relationships of adiponectin, measured by an ELISA (ALPCO). The assay sensitivity is leptin, and visfatin with endometrial cancer risk, we 0.12 ng/mL, and the interassay CVs are 4.7%, 5.7%, and measured prediagnostic serum levels of these adipokines 7.2% at 0.72, 1.01, and 2.92 ng/mL, respectively. Estradiol using a case–control study nested within the Prostate, was measured by RIA following organic solvent extrac- Lung, Colorectal and Ovarian (PLCO) cancer screening tion and Celite column partition chromatography. The trial. We adjusted for body mass index (BMI), estradiol, assay sensitivity is 2 pg/mL and the interassay CVs are and other factors known to influence endometrial cancer 11%, 13%, and 12% at 15, 36, and 101 pg/mL, respectively. risk to determine whether serum adipokine levels are Matched sets were not retained within the same assay independently associated with endometrial cancer. batch; however, the proportion of cases and controls was generally consistent across batches. We did not Materials and Methods observe any systematic drifts in analyte levels based Study population on batch, and adjustment for batch in subsequent anal- The design of the PLCO cancer screening trial has been yses did not significantly