Plasma Adiponectin Concentrations and Risk of Incident Breast Cancer

The Journal of Clinical Endocrinology & Metabolism, Apr 2007

Tworoger, Shelley S., Eliassen, A. Heather, Kelesidis, Theodoros, Colditz, Graham A., Willett, Walter C., Mantzoros, Christos S., Hankinson, Susan E.

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Plasma Adiponectin Concentrations and Risk of Incident Breast Cancer

The Journal of Clinical Endocrinology & Metabolism Plasma Adiponectin Concentrations and Risk of Incident Breast Cancer Shelley S. Tworoger 0 1 A. Heather Eliassen 0 1 Theodoros Kelesidis 0 1 Graham A. Colditz 0 1 Walter C. Willett 0 1 Christos S. Mantzoros 0 1 Susan E. Hankinson 0 1 0 First Published Online 1 Channing Laboratory, Department of Medicine (S.S.T., A.H.E. , G.A.C., W.C.W., S.E.H.) , Brigham and Women's Hospital and Harvard Medical School , Boston , Massachusetts 02115; Departments of Epidemiology (S.S.T., A.H.E. , G.A.C., W.C.W., S.E.H.) and Nutrition (W.C.W.) , Harvard School of Public Health, Boston, Massachusetts 02115; and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine (T.K., C.S.M.), Beth Israel Deaconess Medical Center , Boston, Massachusetts 02215 , USA Introduction: Previous retrospective case-control studies suggest that adiponectin, an obesity-related hormone, is inversely associated with breast cancer risk, particularly in postmenopausal women; however, no prospective studies exist. Therefore, we conducted a prospective case-control study nested within the Nurses' Health Study (NHS) and NHSII cohorts examining the association between plasma adiponectin concentrations and breast cancer risk. Materials and Methods: Blood samples were collected from 1989 through 1990 (NHS) and 1996 through 1999 (NHSII); adiponectin was measured by RIA. The analysis included 1477 breast cancer cases diagnosed after blood collection and before June 2000 (NHS) or June 2003 (NHSII) who had one or two controls (n 2196) matched on age, menopausal status, postmenopausal hormone (PMH) use, fasting, and time of day and month of blood collection. We adjusted for body mass index at age 18, weight change from age 18 to blood draw, family history of breast cancer, history of benign - I NCREASED ADIPOSITY IS a breast cancer risk factor in postmenopausal women ( 1 ). This relationship is mediated, in part, by increased estrogen levels in overweight women as a result of conversion of androgens to estrogens by adipose tissue ( 2 ). Conversely, in premenopausal women, increased body fatness in childhood and adulthood is associated with a decreased breast cancer risk ( 1, 3– 6 ). The mechanism for this relationship is not clear. One mechanism through which body fatness may influence breast cancer risk is through insulin resistance and hyperinsulinemia ( 7 ). Increased fasting insulin and C-peptide levels, both markers for insulin resistance, have been associated with breast cancer in some ( 8 –15 ) but not all (16) studies. Type 2 diabetes may modestly increase breast cancer risk ( 17, 18 ). Adiponectin is an adipocyte-derived peptide hormone that is inversely associated with adiposity ( 7, 19 ). Adiponectin is a strong indicator of insulin sensitivity, and its decline precedes the onset of obesity and insulin resistance (19) and JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community. breast disease, duration of PMH use, ages at menarche and first birth, and parity. Results: Although we observed no association between adiponectin and breast cancer risk overall, there was a nearly significant interaction by menopausal status (P 0.08), with a relative risk, top vs. bottom quartile of 0.73 (95% confidence interval, 0.55–0.98; P trend 0.08) among postmenopausal women and 1.30 (95% confidence interval, 0.80–2.10; P trend 0.09) for premenopausal women. Among postmenopausal women, adiponectin appeared more strongly inversely associated in women who never used PMH (P heterogeneity 0.05) and women with low circulating estradiol levels (P heterogeneity 0.05). Discussion: Our results suggest that adiponectin may be inversely associated with postmenopausal breast cancer risk, particularly in a low-estrogen environment. (J Clin Endocrinol Metab 92: 1510 –1516, 2007) may be one mechanism through which obesity alters breast cancer risk. In three retrospective case-control studies, in which adiponectin levels were measured after diagnosis, adiponectin levels were inversely associated with breast cancer risk ( 20 –22 ); the association appeared stronger for postmenopausal women ( 21 ). Adiponectin levels may be influenced by disease in this type of case-control study, potentially biasing the results. Therefore, using prediagnostic blood samples, we conducted a prospective case-control study nested within the Nurses’ Health Study (NHS) and NHSII cohorts, examining the association between plasma adiponectin concentrations and breast cancer risk overall and by menopausal status. We also examined whether this relationship differed by cancer subtype and other participant characteristics. This study used blood samples obtained before breast cancer cases were diagnosed, hence the prospective design. Subjects and Methods Study population The NHS cohort was established in 1976 among 121,700 U.S. female registered nurses (30 –55 yr), and the NHSII was established in 1989 among 116,609 female registered nurses (25– 42 yr). Women in both cohorts completed and returned an initial questionnaire and have been followed every 2 yr since inception by questionnaire to update exposure variables and ascertain newly diagnosed disease. The racial/ethnic breakdown of the NHS is 96% Caucasian, 2% African-American, 1% Asian, and 1% Hispanic; and in NHSII, it is 94% Caucasian, 2% AfricanAmerican, 2% Asian, and 2% Hispanic. In 1990, 32,826 NHS cohort members, 43 to 69 yr old, provided blood samples [described previously ( 23 )]. Briefly, women arranged to have their blood drawn and shipped with an icepack by overnight courier to our laboratory, where it was processed and separated into plasma, red blood cell, and white blood cell components. At blood collection, women completed a short questionnaire asking about current weight, postmenopausal hormone (PMH) use, and menopausal status. Follow-up of this blood study cohort was 99% in 2000. Between 1996 and 1999, 29,611 NHSII cohort members, 32 to 54 yr old, provided blood samples [described previously ( 24 )]. Briefly, premenopausal women who had not taken hormones, been pregnant, or lactated in the previous 6 months (n 18,521) provided a blood sample drawn on the third through fifth days of their menstrual cycle (follicular draw) and 7 to 9 d before the anticipated start of their next cycle (luteal draw); this study assayed adiponectin in one sample per woman (i.e. luteal draw for women with timed samples). All other women (n 11,090) provided a single 30-ml “untimed” blood sample. Luteal and untimed samples were shipped and processed similarly to the NHS samples. Participants completed a short questionnaire asking about current weight, normal menstrual cycle patterns, and recent medication use. Follow-up of this blood cohort was 98% in 2003. As a result of our processing method, we tested whether delayed processing of plasma altered measurable adiponectin levels. The intraclass correlation of adiponectin comparing 15 samples processed immediately vs. samples processed 24 or 48 h later was 0.97, suggesting that adiponectin is extremely stable with delayed processing. Both the NHS and NHSII studies were approved by the Committee on the Use of Human Subjects in Research at the Brigham and Women’s Hospital. Menopausal status was determined similarly for both studies. A woman was considered to be premenopausal if she 1) gave timed samples, 2) reported that her periods had not stopped, or 3) had a hysterectomy but had at least one ovary remaining and was 47 yr or younger (nonsmokers) or 45 yr or younger (smokers). A woman was considered to be postmenopausal if she 1) reported that her natural menstrual periods had stopped permanently, 2) had a bilateral oophorectomy, or 3) had a hysterectomy but had at least one ovary remaining, and was 56 yr or older (nonsmokers) or 54 yr or older (smokers) ( 25 ). The remaining women, the majority of whom had had a simple hysterectomy and were 48 to 55 yr of age, were of unknown menopausal status. The study population is divided into two data sets, one from each cohort. Each data set contained both premenopausal and postmenopausal women who had no reported cancer diagnosis (except nonmelanoma skin cancer) before blood collection. NHS cases and controls Cases were diagnosed with breast cancer after blood collection but before June 1, 2000. Overall, 1280 cases of breast cancer were reported and confirmed by medical record review (n 1260) or verbal confirmation by the nurse (n 20). As a result of the high confirmation rate in medical record review (99%), these latter cases were included in the analysis. Cases and controls were matched using incidence density, matching on the following: age ( 2 yr), menopausal status at blood draw and diagnosis (premenopausal, postmenopausal, unknown), recent PMH use in the previous 3 months (yes, no), month/year of blood collection ( 1 month), time of day of blood draw ( 2 h), and fasting status (no more than 10 h since last meal, more than 10 h since last meal, and unknown) ( 26 ). For cases who were premenopausal or of unknown menopausal status at blood collection (n 398) or were postmenopausal and reported using PMH within 3 months of blood collection (n 496), one control was matched per case. For postmenopausal cases who did not report recent PMH use at blood collection (n 386), two controls were matched per case. We matched two controls in some subgroups to increase power for other analyses only among those women. NHSII cases and controls Cases were diagnosed with breast cancer after blood collection but before June 1, 2003. Overall, 317 cases of breast cancer were reported and confirmed by medical record review (n 298) or verbal confirmation by the nurse (n 19). Cases were matched using incidence density matching to two controls on the following: age ( 2 yr), menopausal status at blood collection and diagnosis (premenopausal, postmenopausal, unknown), month/year of blood draw ( 1 month), and ethnicity (AfricanAmerican, Asian, Hispanic, Caucasian, other); additionally, for each blood draw, cases and controls were matched on time of day ( 2 h) and fasting status ( 2, 2– 4, 5–7, 8 –11, 12 h since last meal) ( 24 ). Timed (luteal) samples were matched on the luteal day of the blood collection (date of next period date of luteal draw, 1 d). Laboratory assays Adiponectin was assayed by a RIA (Linco Research, St. Charles, MO) at the laboratory of one of the authors (C.S.M.) in four batches. The assay sensitivity was 2 ng/ml. Estradiol, measured in the NHS postmenopausal women and NHSII premenopausal women with follicular and luteal samples, was assayed by sensitive and specific RIA after organic solvent extraction and Celite column partition chromatography ( 27 ). IGF-I was assayed by ELISA in all samples ( 28 ). C-peptide was measured by ELISA (Diagnostic Systems Laboratory, Webster, TX) in NHS cases and controls identified from 1990 to 1996; similarly IGF binding protein-1 (IGFBP-1) was measured via ELISA (Diagnostic Systems Laboratory) in fasting NHS cases and controls identified from 1990 to 1996. All case-control sets were assayed together with a random sample order. Laboratory technicians were blinded to case-control status. Ten samples were run in three of the four batches for adiponectin (the second NHS batch and both NHSII batches); correlations between samples across the different batches were 0.79 to 0.86. We included replicate plasma samples to assess laboratory precision. The coefficient of variation for adiponectin ranged from 7–13% and was less than 12% for estradiol, IGF-I, fasting IGFBP-1, and C-peptide. Statistical analysis We excluded women who were missing adiponectin values as a result of assay difficulties or low sample volume (NHS, n 114 cases and 92 controls; NHSII, n three cases and 11 controls). Seven NHSII women had outlier values (less than 4 g/ml) ( 29 ) and were excluded. Overall, 1477 cases and 2196 controls were available for analysis. Comparison of adiponectin levels by case status was conducted by mixed-effects regression models, controlling for matching factors. Because participants came from similar cohort studies, we combined the data using batch-specific quartile cut points based on control distributions (see Appendix Table A, published as supplemental data on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org) ( 27 ). We used conditional logistic regression to estimate odds ratios and 95% confidence intervals (CIs) comparing quartiles of adiponectin concentrations. The odds ratio appropriately estimates the relative risk (RR) ( 30 ); therefore, we henceforth use the term RR. Based on previous data ( 21 ), we stratified by menopausal status ( 31 ); to have the cleanest comparison, we restricted the study to women who were premenopausal or postmenopausal at both blood draw and diagnosis/ reference date. Because the point estimates were nearly significantly different and given the known variation in the body mass index (BMI)breast cancer relationship by menopausal status, we stratified further analyses by menopausal status. We estimated RRs and 95% CIs comparing adiponectin quartiles for various case groups [in situ vs. invasive, ductal vs. lobular, estrogen receptor/progesterone receptor (ER/PR) status, time between blood draw and diagnosis] using polytomous unconditional logistic regression adjusting for matching factors ( 32 ). To determine whether the RRs for case groups differed, we compared a model holding the association of the adiponectin probit score, calculated for each individual within batches, and breast cancer constant across case groups to one allowing the association to vary using the likelihood ratio test ( 32 ). The probit score ranks individuals within an assay batch (ranks are normally distributed), thus standardizing for between-batch assay variability. Secondary analyses, stratified by age at blood collection, BMI, waist-to-hip ratio (WHR), physical activity, PMH use, and circulating estradiol or IGF-I levels, used unconditional logistic regression adjusting for matching factors. Tests for interaction were conducted by comparing the slope of the probit score between groups through the Wald test. All models were adjusted for the following a priori confounders: BMI at age 18, weight change from age 18 to blood draw, family history of breast cancer, history of benign breast disease, duration of PMH use, age at first birth/parity, and age at menarche. Further adjustment for alcohol intake, physical activity, WHR, duration of oral contraceptive use, or age at menopause did not substantially alter results. We considered additional adjustment for estradiol, IGF-I, C-peptide, and IGFBP-1 levels, in the subset of women with these measures, to determine the independent association of adiponectin with breast cancer. Tests for trend were conducted by modeling probit scores continuously and calculating the Wald statistic ( 33 ). P values were based on two-sided tests and considered significant if 0.05 or less. Results Participants were 32 to 70 yr old at blood collection (mean age, NHS, 58 yr; NHSII, 45 yr; Table 1). In both studies, more cases than controls had a family history of breast cancer (16.4% vs. 10 –11%) and a history of benign breast disease. Differences for other characteristics between cases and controls generally were small, although in the expected direction. In the NHS, cases had median adiponectin levels similar to controls (P 0.44), and in the NHSII, cases had higher median levels than controls (P 0.02), although there were fewer women in the NHSII vs. the NHS. The correlation between adiponectin and BMI was 0.26 for premenopausal women and 0.24 for postmenopausal women and with WHR was 0.18 and 0.23, respectively. Although there was no clear association overall between plasma adiponectin concentrations and breast cancer risk, there was a nearly statistically significant interaction by menopausal status (P 0.08) such that the RR, top vs. bottom quartile, for premenopausal women was 1.30 (95% CI, 0.80 – 2.10; P trend, 0.09) and for postmenopausal women was 0.73 (95% CI, 0.55– 0.98; P trend, 0.08) (Table 2). The results were similar when stratifying by menopausal status at blood collection (data not shown). Among postmenopausal women, additional adjustment for estradiol did not change the results, even when not adjusting for BMI at age 18 and weight change from age 18 to blood draw (RR, top vs. bottom quartile, 0.74; 95% CI, 0.55–1.01; P trend, 0.12). Adjustment for IGF-I, C-peptide, and IGFBP-1 levels did not change risk estimates; for example, among women with measured Cpeptide levels, the RR comparing the top vs. bottom adiponectin quartile was 0.66 before adjustment for C-peptide and 0.70 after adjustment for C-peptide levels. Among premenopausal women, results were similar after adjustment for IGF-I or estradiol levels (data not shown). Results were similar when including the small number of women with outlier values of adiponectin (data not shown). Among postmenopausal women, the relationship between adiponectin and breast cancer varied by ductal vs. lobular cancers (P heterogeneity 0.04), although the number of lobular cancers was small (Table 3). There was no association for lobular cancers (P trend 0.22), but there was a modest inverse association for ductal cancers (P trend 0.07) with a RR 0.75 (95% CI, 0.55–1.01) comparing the top vs. bottom quartiles. We did not observe differences by in situ vs. invasive status, ER/PR status, or time between blood draw and diagnosis (data not shown). Among postmenopausal women, we observed statistically significant interactions (P interaction 0.05) between adiponectin and PMH use (never vs. ever) and circulating estradiol levels in relation to breast cancer risk (Table 4). There was a linear inverse association among never PMH users Data represent mean (SD), unless described otherwise. a P value comparing mean or percentage between cases and controls within study with the exception of matching factors (noted as NA). b Matching factor; because postmenopausal cases not using PMH were matched 1:2 and other cases were matched 1:1, the controls in the NHS appear slightly older on average, have a slightly higher percentage of postmenopausal women, and a higher percentage of women who were never or were past users of PMHs than cases. c Among parous women only. d Among women who were postmenopausal at blood draw. Unadjusted modelb Multivariate modelb,c Premenopausal at blood draw and diagnosisb,c,d Postmenopausal at blood draw and diagnosisb,c,d (RR, top vs. bottom quartile 0.57; 95% CI, 0.35– 0.93; P trend, 0.01), but no trend among ever users (RR 0.90; 95% CI, 0.65–1.25; P trend, 0.82). Among never PMH users, additional adjustment for estradiol substantially attenuated the association (RR 0.90; 95% CI, 0.46 –1.75; P trend, 0.45); however, there were small numbers of cases in this analysis (n 167) and a correlation of 0.27 between adiponectin and estradiol, possibly causing instability in the estimate. Women with circulating estradiol levels below the median (using batch-specific control distributions) had a stronger inverse association between adiponectin and breast cancer risk (P trend 0.04) than those with levels above the median (P trend 0.51). This result persisted after additional adjustment for continuous ln-transformed estradiol levels. Although the association did not significantly differ by BMI, WHR, age, or IGF-I levels (data not shown), there was a suggestion of a stronger inverse association for women with lower BMI. Among premenopausal women, results did not vary by age, BMI, WHR, luteal estradiol levels, or by case characteristics (all, P heterogeneity 0.10 or greater). There was a suggestion of a positive association between adiponectin and breast cancer risk among cases diagnosed less than 2 yr after blood collection vs. 2 to 4 or 4 yr (P heterogeneity 0.02); the RRs comparing the top vs. bottom quartiles were 2.00, 1.30, and 0.89, respectively. Discussion To our knowledge, this is the first prospective study examining plasma adiponectin concentrations and risk of breast cancer with 1477 incident breast cancer cases. We observed an inverse association between adiponectin and postmenopausal breast cancer risk that was likely independent of estrogen levels overall but observed no clear association in premenopausal women. Furthermore, the association between adiponectin and postmenopausal breast cancer risk remained after adjustment for markers of insulin resistance including C-peptide, a marker of insulin secretion ( 34 ), and IGFBP-1, which is negatively regulated by insulin ( 35 ). In postmenopausal women, the association appeared stronger in ductal vs. lobular cancers and among never users of PMH and those with low circulating estradiol concentrations. Similar to our findings, three previous retrospective casecontrol studies (n 100 –174 cases) reported inverse associations between adiponectin concentrations and breast cancer risk ( 20 –22 ). Furthermore, one of these studies ( 21 ) only a Adjusted for BMI at age 18, weight change from age 18 to blood draw, family history of breast cancer, history of benign breast disease, duration of PMH use, age at first birth/parity, age at menarche, assay batch, and matching factors. b Determined using batch-specific probit scores. c Determined using polytomous logistic regression and the likelihood ratio test comparing a model constraining relative risks to be the same across all case groups vs. a model allowing the relative risks to differ across case groups. a Adjusted for BMI at age 18, weight change from age 18 to blood draw, family history of breast cancer, history of benign breast disease, duration of PMH use, age at first birth/parity, age at menarche, assay batch, and matching factors. b Determined using batch-specific probit scores. c Determined using the Wald test, comparing trends of batch-specific probit scores between the reference stratum and the other strata. d Results were similar when including only women not taking PMH at blood collection. observed an association in postmenopausal women, which is consistent with our findings, although another study reported a similar association by menopausal status ( 22 ). However, both studies ( 21, 22 ) had a small number of premenopausal cases (n 49 and 52, respectively). It is possible that the association is not apparent among premenopausal women because BMI is inversely associated with breast cancer risk in this population (1). In fact, our results suggest that adiponectin could be positively associated with premenopausal breast cancer risk, although the relative risk was not statistically significant. Although we did observe a significantly higher median adiponectin in NHSII cases vs. controls, comprised of predominantly premenopausal women, this association may be the result of chance given the relatively smaller numbers compared with the NHS and thus needs to be reevaluated in larger studies. Although there are no supporting data to our knowledge, it is also possible that adiponectin may have a different effect on premenopausal breast tissue (e.g. high estrogenic and progesterone environment) than postmenopausal tissue. Previous studies have suggested a weak link between insulin resistance and type 2 diabetes and breast cancer risk ( 8, 10 –15, 17, 18 ). Similar to our results, in the only prospective study to date ( 17 ), the association between type 2 diabetes and breast cancer risk was only observed among postmenopausal but not premenopausal women. Adiponectin concentrations are strongly, inversely associated with insulin resistance and are an excellent marker of insulin sensitivity ( 7, 19, 36, 37 ). In total, the results from this and previous studies suggest that increased adiponectin may be inversely associated with postmenopausal breast cancer risk; however, the association in premenopausal women remains unclear. Data from experimental models suggest a biological role of adiponectin in mammary carcinogenesis ( 38 ). Adiponectin appears to reduce proliferation of several cells types, including smooth muscle cells ( 19, 39 ), endothelial cells (39), several myeloid cell lines ( 40 ), and breast cancer cells ( 41 ) possibly by binding mitogenic growth factors ( 41, 42 ). Furthermore, in a macaque model, higher adiponectin levels were associated with a decreased percentage of cells with positive Ki-67 staining, a marker of cell proliferation (43). Adiponectin also appears to inhibit vascular endothelial growth factor-induced cell migration ( 39 ). Several studies have suggested that adiponectin may have antiinflammatory effects by inhibiting TNF- -induced expression of adhesion molecules ( 37 ) and by down-regulating TNF- expression by macrophages ( 40 ). Finally, adiponectin induces apoptosis ( 39 – 41 ), may have an antiangiogenic effect in vitro and in vivo ( 39 ), and may be involved in cell signaling pathways associated with carcinogenesis ( 42 ). Although experimental data suggest that adiponectin has antitumor effects, it is also possible that adiponectin may be a marker for another, as of yet, unidentified breast cancer risk factor. In this study, we found that the relationship between adiponectin levels and breast cancer significantly differed by ductal vs. lobular type among postmenopausal women. Specifically, there was a modest association with ductal, but not lobular, tumors. To our knowledge, there are no biological data supporting this association. Because none of the previous studies examined this relationship, these results should be interpreted with caution, especially because we had a relatively small number of lobular tumors. Similar to previous studies ( 20, 22 ), we did not find any differences in association by invasiveness or ER/PR status. Among premenopausal women, there was a positive association for cases diagnosed within 2 yr of blood collection. This is inconsistent with data from Miyoshi et al. (22), which found that, among patients with breast cancer, those with lower adiponectin levels had a higher histological grade. A possible reason for the association observed in our study is that breast tumors may produce adiponectin and increase circulating levels, although Tessitore et al. ( 44 ) reported that, in vitro, breast cancer cells do not secrete adiponectin. It is also possible that breast adipose tissue produces adiponectin, which may have a local effect. We also found that the association between adiponectin and postmenopausal breast cancer was strongest among women who had never used PMH and those with low circulating estradiol levels. These results suggest that adiponectin may only influence breast cancer etiology in a lowestrogen environment. Although it is possible that the antiproliferative action of adiponectin cannot overcome the strong proliferative effect of estrogens on breast tumors, one study of MCF-7 cells suggested that adiponectin reduced proliferation in response to estradiol exposure ( 41 ). However, given that adjustment for estradiol levels attenuated the association among never PMH users and until these results are replicated in other prospective studies, our results should be interpreted with caution. We did not observe any effect modification by circulating IGF-I levels, suggesting that this pathway does not interact with adiponectin in relation to breast cancer risk. This study has several limitations. High- and low-molecular-weight forms of adiponectin circulate in human plasma, which may have different biological activities ( 45– 47 ). The assay used in this study identifies total adiponectin and cannot distinguish between the two forms. Also, it is possible we have residual confounding by adiposity or other factors associated with adiposity, such as estradiol levels, despite careful adjustment in multivariate models. Also, given that our population is primarily Caucasian, our results may not be applicable to other racial/ethnic groups. Although we adjusted for C-peptide and IGFBP-1 levels, we were not able to adjust directly for insulin resistance using the homeostasis model of assessment index. It is possible then that the associations we observed may be mediated by insulin resistance; this possibility should be explored in future studies. Despite these limitations, this was a prospective study with over 300 premenopausal cases and 850 postmenopausal cases, although we had limited power to examine interactions in premenopausal women. To our knowledge, this is the first prospective study of the relationship between plasma adiponectin concentrations and risk of breast cancer in premenopausal and postmenopausal women. Our results suggest that there is an inverse association among postmenopausal women but that there is little or no association among premenopausal women. Our study lends support to the hypothesis that adiponectin may play a role in breast cancer etiology, particularly in a low-estrogen environment; however, further confirmation in other prospective studies is needed before a causal inference can be made. Also, given the known inverse relationship between BMI and premenopausal breast cancer risk, it will be important to continue to study the association of adiponectin with premenopausal breast cancer risk. In conclusion, our results provide continuing evidence of a role of high BMI in postmenopausal breast cancer risk; postmenopausal women should be encouraged to lose weight as one method to decrease their risk of breast cancer. Acknowledgments This work was supported by National Institutes of Health Grants P01 CA87969, CA49449, CA67262, and DAMD-17-02-1-0692. 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Tworoger, Shelley S., Eliassen, A. Heather, Kelesidis, Theodoros, Colditz, Graham A., Willett, Walter C., Mantzoros, Christos S., Hankinson, Susan E.. Plasma Adiponectin Concentrations and Risk of Incident Breast Cancer, The Journal of Clinical Endocrinology & Metabolism, 2007, 1510-1516, DOI: 10.1210/jc.2006-1975