Endocrine-Related Cancer (2007) 14 669–677
Anthropometric measures, plasma adiponectin, and breast cancer risk Yu-Feng Tian, Chi-Hong Chu1, Mei-Hsuan Wu 2, Chia-Lin Chang 3, Tsan Yang 4, Yu-Ching Chou3, Giu-Cheng Hsu5, Cheng-Ping Yu6, Jyh-Cherng Yu7 and Chien-An Sun3 Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan 1 Headquarter, National Defense Medical Center, Taipei, Taiwan 2 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 3 School of Public Health, National Defense Medical Center, Taipei, Taiwan 4 Graduate Institute of Health Care, Meiho Institute of Technology, Pingtung, Taiwan 5 Department of Radiology, Tri-Service General Hospital, Taipei, Taiwan 6 Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan 7 Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan (Correspondence should be addressed to C-A Sun; Email:
[email protected]) Y-F Tian and C-H Chu contributed equally to this paper
Abstract Adiponectin is a peptide hormone secreted exclusively by adipocytes, and obesity is an established risk factor for breast cancer. We have, thus, evaluated the associations of anthropometric measures of adiposity and adiponectin with the development of breast cancer in a case–control study. Questionnaire information, anthropometric measures, and blood samples were taken before treatment from 244 incident cases with breast cancer, including 141 premenopausal and 103 postmenopausal cases, and 244 controls admitted for health examination at the Tri-Service General Hospital, Taipei between 2004 and 2005. Plasma levels of adiponectin were measured by RIA. The relationship between anthropometric measures of adiposity and breast cancer risk was modified by menopausal status, with a significant increase in risk observed in postmenopausal but not premenopausal women. Moreover, a fairly robust inverse association of adiponectin with the risk was observed only in postmenopausal women (adjusted odds ratio (OR), 0.55; 95% confidence interval (CI), 0.23–0.97), but not in premenopausal women. Additionally, the plasma adiponectin levels tended to be inversely associated with estrogen receptor (ER)-positive (adjusted OR, 0.53; 95% CI, 0.27–0.98) but not ER-negative breast tumors. Furthermore, the associations of adiponectin with breast cancer risk overall and by menopausal and ER status remained after adjustment for obesity indices. These results suggest that adiponectin may have an independent role in breast carcinogenesis, particularly in the postmenopausal and ER-positive breast cancer risk. Endocrine-Related Cancer (2007) 14 669–677
Introduction Evidence is accumulating that obesity and insulin resistance are implicated in the etiology of breast cancer (Rose et al. 2004). Adipose tissue is the site of peripheral aromatization of adrenal androgens to estrogens (Bulun et al. 1994), and obesity-related elevations in estrogens have been associated with increased breast cancer risk (Yager & Davidson 2006). A strong association of obesity with insulin resistance has also been welldocumented (Haslam & James 2005). There is evidence
that insulin and insulin-like growth factors may play an important mitogenic role in the pathogenesis of breast cancer (Rose et al. 2004, Fletcher et al. 2005). It has been indicated that the adipose tissue is not only a fat-storing tissue but also an endocrine organ secreting various cytokines, including adiponectin. Adiponectin is a recently identified adipocyte-secreted hormone (Chandran et al. 2003). Adiponectin stimulates the sensitivity of peripheral tissues to insulin, and its circulating levels are low in conditions characterized by insulin-resistant states, such as obesity and
Endocrine-Related Cancer (2007) 14 669–677 1351–0088/07/014–669 q 2007 Society for Endocrinology Printed in Great Britain
DOI:10.1677/ERC-06-0089 Online version via http://www.endocrinology-journals.org
Y-F Tian, C-H Chu et al.: Adiposity, adiponectin, and breast cancer type 2 diabetes (Arita et al. 1999, Weyer et al. 2001). Because these conditions are also recognized risk factors for breast cancer (Rose et al. 2004, Wolf et al. 2005), we have hypothesized that circulating levels of adiponectin might underlie the observed associations between breast cancer and obesity. To test this hypothesis, we have conducted a case–control study of 244 women with newly diagnosed, histologically confirmed breast cancer and 244 control women.
Materials and methods Case and control selection
This case–control study was conducted at the Tri-Service General Hospital, Taipei, Taiwan, from January 2004 to December 2005. Based on the hospital chart number, the cases involved 244 women consecutively selected from subjects with a first confirmed histopathologic diagnosis of breast carcinoma in the age range of 22–87 years. The histopathological profile included 173 cases of infiltrating ductal carcinoma and 71 cases of intraductal or intralobular carcinoma. Overall, 44 of the cases were in situ and 195 of the cases were invasive. In addition, there were 141 premenopausal and 103 postmenopausal cases with breast cancer. The data on the status of estrogen receptor (ER) of breast tumors were obtained from the Department of Pathology of the Tri-Service General Hospital that routinely conduct biochemical assays to determine the ER status of tumor tissues from breast cancer patients. Accordingly, ER status was known for 205 (84%) out of the 244 cases. For women with known receptor status, 150 (73%) were ER-positive and 55 (27%) were ER-negative. Additionally, the proportion of ER-positive in pre- and postmenopausal cases with breast cancer was 74% and 72%, respectively. Control subjects comprising individuals without a history of cancer were simultaneously recruited from the health examination clinics of the same hospital during the same study period. One control subject was matched to each case by menopausal status, date of enrollment (G3 months), and duration of fasting (G4 h). There were 244 case–control sets included in this study. Collection of questionnaire data and blood specimens
Once case patients and control subjects agree to participate, written informed consent was obtained from all subjects. The research protocol was approved by the Institutional Review Board at the Tri-Service General Hospital, Taipei. All participants underwent personal interview administered by well-trained interviewers in conformance with institutional guidelines 670
for studies including human subjects. Data were collected on sociodemographic characteristics, menstrual and reproductive history, menopausal status, lifestyle behaviors and medical history as well as family history of breast, and other cancers. More specifically, in this study, menopausal status was defined as last menstruation after 1 year free of menstrual cycle, and no attempt was made to distinguish between women with artificial and those with natural menopause. Immediately after the interview, a 10 ml blood sample was drawn into coded EDTA-treated tubes and centrifuged at 1467 g for 10 min at room temperature within 10 h of collection. Plasma, buffy coat, and red blood cells were separated and stored at K70 8C until subsequent analysis. Because questionnaire data and biospecimens were obtained prior to cases’ acceptance with surgery and radio- or chemotherapy, any influence of treatment is unlikely. Anthropometric measurements and laboratory analysis of plasma adiponectin levels
Participants reported information regarding height and weight. Body mass index (BMI), as an indicator of generalized obesity, was calculated as weight in kilograms divided by the square of height in meters. In addition, measurements of waist and hip circumferences were performed by trained clinical staff using standardized techniques. Waist girth was determined with a measuring tape placed horizontally around the midpoint between the iliac crest and lower margin of the ribs. Hip girth was the maximum circumference around the buttocks posteriorly and the symphysis pubis anteriorly. As a result, waist-to-hip ratio (WHR) represents a measure of central adiposity. Plasma adiponectin concentrations were measured in a single run using a commercially available RIA kit (R&D systems Inc., Minneapolis, MN, USA) according to manufacturer’s instructions. Adiponectin standards were prepared using recombinant human adiponectin, with a sensitivity of 0.25 ng/ml and intra- and interassay coefficients of variation of 3.53% and 6.50%, respectively. All matched case–control blood samples were handled identically and assayed in the same analytical run. The blood samples were labeled by number only and ordered randomly within each case– control pair. Accordingly, laboratory personnel were unaware of the case–control status. Statistical analysis
Differences between cases and controls in age at menarche, age at first full-term pregnancy, age at www.endocrinology-journals.org
Endocrine-Related Cancer (2007) 14 669–677 menopause, and parity numbers were tested using the Student’s t-test. Because the average quantity of cigarettes and alcohol consumed by Chinese women is not large in Taiwan, habitual cigarette smoking was defined as smoking cigarettes at least once a week for more than 1 year. Similarly, habitual alcohol drinking was defined as consuming any alcoholic beverage at least once a week for more than 1 year. Distributions in cigarette smoking and alcohol intake status, menopausal status, as well as use of oral contraceptives between cases and controls were evaluated using the chi squared test. Conditional logistic regression, which preserves the matching of cases and controls, was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the plasma adiponectin levels and breast cancer risk.
Results The baseline characteristics of cases and controls are summarized in Table 1. The mean age (GS.D.) of the cases and controls was 51.5(G11.4) and 48.4(G7.9) years, respectively. There were no significant differences between cases and controls in terms of age at menarche (13.9G1.6 vs 13.6G1.5 years), age at first full-term pregnancy (25.9G4.2 vs 26.7G3.7 years), age at menopause (49.5G5.3 vs 48.9G4.8 years), and parity number (2.6G1.4 vs 2.2G0.8). No significant differences were also found between cases and controls in terms of the proportions of women with cigarette smoking (7.8% vs 4.9%), alcohol drinking (11.1% vs 13.5%), and use of oral contraceptives in premenopausal period or hormone replacement therapy in postmenopausal period (15.9% vs 15.9%). When subjects were subdivided by menopausal status, cases and controls were similar in their
distribution of most of the aforementioned variables. However, postmenopausal cases with breast cancer were significantly older than their matched controls (PZ0.0012). The distribution of anthropometric characteristics and ORs for breast cancer by logistic regression is shown in Table 2. Overall, a measure of central adiposity as reflected by WHR was significantly related to breast cancer risk (adjusted OR, 2.17; 95% CI, 1.42–3.32; between subjects in the top tertile and those below the highest tertile). Additionally, in the subgroup analysis stratified by menopausal status, we found that the risk for breast cancer increases with larger anthropometric measures including BMI (adjusted OR, 2.94; 95% CI, 1.53–5.68), waist circumference (adjusted OR, 2.02; 95% CI, 1.05–3.91), and WHR (adjusted OR, 3.64; 95% CI, 1.88–7.05) in postmenopausal women. However, no any anthropometric characteristic was significantly associated with risk in premenopausal women. To evaluate the relationships of plasma adiponectin levels with anthropometric measures of adiposity, we performed a correlation analysis among control subjects. Plasma adiponectin was significantly inversely correlated with BMI (Spearman rZK0.32, PZ0.0001), waist circumference (rZK0.35, PZ0.01), and WHR (rZK0.32, PZ0.0001). We further categorized plasma adiponectin as high or low levels based on the 75 percentile in the control group for subsequent analyses. Table 3 shows the association of breast cancer with plasma adiponectin levels. In a conditional logistic regression model that were adjusted for age at enrollment, date at enrollment, fasting, and menopausal status as well as BMI, and WHR, women in the high adiponectin level had a
Table 1 Characteristics of breast cancer cases and their matched controls at enrollment Premenopausal Baseline characteristics
Cases
Number of subjects 141 Mean (S.D.) Age at enrollment (years) 44.4 (6.3) Age at menarche (years) 13.5 (1.4) Age at first birth (years) 27.5 (3.7) Age at menopause (years) Number of parity 1.9 (0.9) Percentage Cigarette smoking 9.9 Alcohol intake 14.9 Premenopausal oral contraceptive 14.2 use or postmenopausal HRT
Postmenopausal
All
Controls
Cases
Controls
Cases
Controls
141
103
103
244
244
43.7 (5.5) 13.3 (1.4) 27.4 (3.7)
61.2 (9.4) 14.5 (1.7) 24.0 (4.0) 49.5 (5.3) 3.3 (1.5)
54.8 (5.9) 14.0 (1.5) 25.8 (3.5) 48.9 (4.8) 2.5 (0.9)
51.5 (11.4) 13.9 (1.6) 25.9 (4.2)
48.4 (7.9) 13.6 (1.5) 26.7 (3.7)
0.118 0.249 0.172
2.6 (1.4)
2.2 (0.8)
0.708
2.0 (0.7) 5.7 12.8 15.6
4.9 5.9 18.4
3.9 14.6 16.5
7.8 11.1 15.9
4.9 13.5 15.9
P value
0.260 0.501 1.000
HRT, hormone replacement therapy.
www.endocrinology-journals.org
671
Y-F Tian, C-H Chu et al.: Adiposity, adiponectin, and breast cancer Table 2 Association of anthropometric measures of adiposity with breast cancer risk, stratified by menopausal status Anthropometric measuresa All women Body mass index (kg/m2) %24.61 O24.61 Waist circumference (cm) %79.25 O79.25 Hip circumference (cm) %99.00 O99.00 Waist-to-hip ratio %0.82 O0.82 Premenopausal women Body mass index (kg/m2) %24.65 O24.65 Waist circumference (cm) %77.50 O77.50 Hip circumference (cm) %99.00 O99.00 Waist-to-hip ratio %0.81 O0.81 Postmenopausal women Body mass index (kg/m2) %24.45 O24.45 Waist circumference (cm) %81.00 O81.00 Hip circumference (cm) %99.00 O99.00 Waist-to-hip ratio %0.82 O0.82
Cases (nZ244) no. (%)
Controls (nZ244) no. (%)
OR (95% CI)
172 (70.49) 72 (29.51)
183 (75.00) 61 (25.00)
1.00 (reference) 1.14b (0.74–1.76)
160 (65.84) 83 (34.16)
183 (75.00) 61 (25.00)
1.00 (reference) 1.39b (0.90–2.15)
186 (76.86) 56 (23.14)
184 (75.41) 60 (24.59)
1.00 (reference) 0.86b (0.56–1.33)
136 (56.20) 106 (43.80)
184 (75.41) 60 (24.59)
1.00 (reference) 2.17b (1.42–3.32)
116 (82.27) 25 (17.73)
106 (75.18) 35 (24.82)
1.00 (reference) 0.60c(0.32–1.09)
104 (73.76) 37 (26.24)
107 (75.89) 34 (24.11)
1.00 (reference) 1.10c(0.63–1.94)
114 (81.43) 26 (18.57)
106 (75.18) 35 (24.82)
1.00 (reference) 0.68c (0.38–1.21)
96 (68.57) 44 (31.43)
107 (75.89) 34 (24.11)
1.00 (reference) 1.40c (0.81–2.41)
54 (52.43) 49 (47.57)
78 (75.73) 25 (24.27)
1.00 (reference) 2.94c (1.53—5.68)
54 (52.94) 48 (47.06)
78 (75.73) 25 (24.27)
1.00 (reference) 2.02c (1.05–3.91)
72 (70.59) 30 (29.41)
78 (75.73) 25 (24.27)
1.00 (reference) 1.17c (0.59–2.33)
40 (39.22) 62 (60.78)
78 (75.73) 25 (24.27)
1.00 (reference) 3.64c (1.88–7.05)
OR, odds ratio; CI, confidence interval. a Categorized by the third quartile value in the control group. b Adjusted for age at enrollment, date at enrollment, fasting status, menopausal status, and levels of adiponectin. c Adjusted for age at enrollment, date at enrollment, fasting status, and levels of adiponectin.
non-significant 25% lower risk of breast cancer than those in the low level (adjusted OR, 0.75; 95% CI, 0.42–1.34). In the subset analysis according to the menopausal status, premenopausal women in the high adiponectin level showed non-significant decrease in breast cancer risk when compared with those in the low level (adjusted OR, 0.84; 95% CI, 0.46–1.52), while postmenopausal women in the high level showed a significantly decreased risk for breast cancer compared with those in the low level (adjusted OR, 0.55; 95% CI, 0.23–0.97). 672
The association between the plasma adiponectin levels and breast cancer risk according to clinicopathological characteristics in breast cancer patients is shown in Table 4. A statistically significantly inverse association between adiponectin levels and breast cancer risk was observed in ER-positive (adjusted OR, 0.53; 95% CI, 0.27–0.98) but not ER-negative breast cancer patients. Furthermore, no significant relationship between plasma levels of adiponectin and breast cancer risk was observed in the subset analysis according to the histology of breast tumors. www.endocrinology-journals.org
Endocrine-Related Cancer (2007) 14 669–677 Table 3 Relationship between plasma adiponectin levels and breast cancer risk Adiponectin levela (mg/ml) All women Low (%14.05) High (O14.05) Premenopausal women Low (%13.37) High (O13.37) Postmenopausal women Low (%15.69) High (O15.69)
Cases no. (%)
Controls no. (%)
OR (95% CI)
190 (77.9) 54 (22.1)
183 (75.3) 60 (24.7)
1.00 (reference) 0.75b (0.42–1.34)
111 (78.7) 30 (21.3)
106 (75.2) 35 (24.8)
1.00 (reference) 0.84c (0.46–1.52)
90 (87.4) 13 (12.6)
77 (75.5) 25 (24.5)
1.00 (reference) 0.55c (0.23–0.97)
OR, odds ratio; CI, confidence interval. a Categorized by the third quartile value in the control group. b Adjusted for age at enrollment, date at enrollment, fasting status, menopausal status, body mass index, and waist-to-hip ratio. c Adjusted for age at enrollment, date at enrollment, fasting status, body mass index, and waist-to-hip ratio.
Discussion Data from the present study confirm previous findings that the relationship between anthropometric measures of adiposity and breast cancer risk was modified by menopausal status, with higher BMI, waist circumference, and WHR associated with increased risk for postmenopausal women (Ng et al. 1997, Huang et al. 1999, Shu et al. 2001, Morimoto et al. 2002, Harvie et al. 2003, Lahmann et al. 2004, Modugno et al. 2006, Rinaldi et al. 2006). The possible biological mechanism underlying excess adiposity and postmenopausal breast cancer risk is that increased adiposity tends to be associated with higher circulating levels of estrogens through greater peripheral conversion of androgens to estrogens by aromatase in adipose tissue among postmenopausal obese women (Silteri 1987, Potischman et al. 1996). In addition, excess adiposity, especially increased abdominal fat, causes insulin resistance and
chronically elevated blood insulin levels, which in turn lower the hepatic synthesis and blood levels of sex hormone-binding globulin (SHBG; Kirschner et al. 1990, Kaaks 1996, Calle & Kaaks 2004). The corresponding hyperestrogenic state resulting from increase in non-SHBG-bound bioactive estradiols may contribute to increased risk for breast cancer. As obesity has been associated with the development of breast cancer, adipocytokines, a group of polypeptide growth factors and cytokines which are produced exclusively by adipose tissue, may underlie the association between obesity and breast cancer risk. Adiponectin is a protein hormone secreted exclusively by adipocytes (Chandran et al. 2003), and circulating adiponectin levels are inversely associated with the risk of obesity-related malignancies, including endometrial cancer (Petridou et al. 2003, Dal Maso et al. 2004, Soliman et al. 2006), breast cancer (Miyoshi et al. 2003, Mantzoros et al. 2004, Tworoger et al. 2007), colon
Table 4 Association of plasma adiponectin levels with breast cancer risk according to clinicopathological characteristics in breast cancer patients Adiponectin level (mg/ml)a ER-positive Low (%15.02) High (O15.02) ER-negative Low (%13.23) High (O13.23) In situ cancers Low (%15.37) High (O15.37) Invasive cancers Low (%13.95) High (O13.95)
ORb (95% CI)
Cases no. (%)
Controls no. (%)
129 (86.00) 21 (14.00)
112 (75.17) 37 (24.83)
1.00 (reference) 0.53 (0.27–0.98)
37 (67.27) 18 (32.73)
42 (76.36) 13 (23.64)
1.00 (reference) 1.81 (0.66–5.00)
33 (75.00) 11 (25.00)
33 (75.00) 11 (25.00)
1.00 (reference) 1.20 (0.40–3.57)
154 (78.97) 41 (21.03)
146 (75.26) 48 (24.74)
1.00 (reference) 0.85 (0.49–1.45)
OR, odds ratio; CI, confidence interval. a Categorized by the third quartile value in the control group. b Adjusted for age at enrollment, date at enrollment, fasting status, menopausal status, body mass index, and waist-to-hip ratio.
www.endocrinology-journals.org
673
Y-F Tian, C-H Chu et al.: Adiposity, adiponectin, and breast cancer cancer (Wei et al. 2005), and leukemia (Petridou et al. 2006). Similar to previous studies (Miyoshi et al. 2003, Mantzoros et al. 2004, Tworoger et al. 2007), the current study showed that plasma adiponectin levels are inversely associated with breast cancer risk. Interestingly, the results of this study demonstrate an inverse association of adiponectin with the risk of postmenopausal but not premenopausal breast cancer, which were in agreement with previous studies (Mantzoros et al. 2004, Tworoger et al. 2007). However, Miyoshi et al. (2003) conducted a case– control study on 102 breast cancer patients and 100 healthy women and observed a similar association by menopausal status. The authors are unable to explain fully the discrepant findings between studies. It has recently emerged that the bioactivity of adiponectin is dependent on its isoform (Trujillo & Scherer 2005) and ethnic variation in adiponectin isoform distribution has been documented (Retnakaran et al. 2006). Thus, it is reasonable to hypothesize that the inconsistent results may be due to differences in ethnicity between studies. Alternatively, one could hypothesize that discrepancies between studies may relate to differences in lifestyle factors between populations. The apparent differences in the association between adiponectin levels and breast cancer risk in pre- and postmenopausal periods need to be studied further. Indeed, previous epidemiological studies have shown an association of obesity and insulin resistance mainly with postmenopausal breast cancer (Stoll 2002, Michels et al. 2003). Finding a significant inverse relationship between adiponectin and breast cancer risk among postmenopausal women in this and previous studies (Mantzoros et al. 2004, Tworoger et al. 2007) provides further support for the importance of adiponectin in the pathogenesis of malignancies associated with obesity-induced insulin resistance and hyperinsulinemia. Moreover, the plasma adiponectin levels were found to be inversely associated with ER-positive but not ER-negative breast cancer risk in the present investigation. Although most epidemiological research has viewed breast cancer as a single disease that is associated with a common set of risk factors, a recent systematic review of the literature has provided evidence that breast cancer are heterogenous (Althuis et al. 2004), which is in agreement with clinical, pathologic, and molecular evidence (Tavassoli 2003). That is, hormonal factors including reproductionrelated exposure and postmenopausal obesity tended to be associated with increased risk of ER-positive but not ER-negative breast cancer (Althuis et al. 2004). Moreover, adiponectin has been shown to be inversely associated with estrogen levels (Gavrila et al. 2003). 674
Thus, it is reasonable to speculate that adiponectin modulates the hormone-related breast cancer risk. The mechanism through which adiponectin modulate breast cancer risk is currently unknown. It has been noted that adiponectin stimulates the sensitivity of peripheral tissue to insulin, and decreased levels of adiponectin are associated with increased serum insulin levels, which accompany insulin resistance (Cnop et al. 2003). Insulin has been shown to stimulate the proliferation of breast cancer cells by binding and signaling through the insulin and insulinlike growth factor I (IGF-I) receptors (Milazzo et al. 1992, Lai et al. 2001). In addition, insulin may synergize with the mitogenic effects of estrogen (van der Burg et al. 1988) and may also upregulate the expression of vascular endothelial growth factor (VEGF), a potent angiogenic agent that is secreted by breast cancer cells (Bachelder et al. 2002). Moreover, adiponectin has been inversely associated with estrogen levels (Gavrila et al. 2003). It remains possible that adiponectin may influence breast cancer risk by altering circulating estrogen levels. It is thus reasonable to hypothesize that the reduced adiponectin levels increase the risk of postmenopausal breast cancer and ER-positive breast tumors through a mitogenic effect of hyperinsulinemia and increased IGFs and estrogen levels as well as by upregulating VEGF. Furthermore, it has been shown that adiponectin potently inhibits endothelial cell proliferation and migration, and induces a cascade of activation of caspases-8, -9, and -3, which leads to cell death (Brakenhielm et al. 2004). Additionally, it has been found that treatment with adiponectin is able to modulate apoptosis of human breast cancer cells in vitro (Korner et al. 2006, Pfeiler et al. 2006) and may be involved in cell signaling pathways associated with carcinogenesis (Kelesidis et al. 2006). These findings suggest other possible mechanisms underlying reduced adiponectin and breast cancer risk. Of particular note, the associations between plasma adiponectin concentrations and breast cancer risk overall and by menopausal and ER status remained after adjustment for obesity indices in the current study. In other words, the inverse associations with adiponectin level were independent of measures of adiposity. Likewise, the associations between measures of adiposity and breast cancer risk remained after adjustment for plasma adiponectin levels. These results seem to suggest a possibility that obesity and adiponectin have independent roles in breast cancer risk and the two mechanisms, possibly reflecting excess estrogen levels and insulin resistance, have multiplicative effects in breast carcinogenesis. www.endocrinology-journals.org
Endocrine-Related Cancer (2007) 14 669–677 Although our study was hospital based, it is unlikely that bias and confounding substantially influenced the main findings. The catchment areas of cases and controls were similar, and interview and blood collection were made in the majority of study subjects on the first day of hospital admission and for cancer cases always before surgical or radiation treatment. In addition, the distributions of plasma adiponectin among cases and controls in this study were similar to findings from a previous Taiwanese study (Chen et al. 2005). The limitation of the present study lies in that this is a case–control study, and blood samples were obtained from cases with breast cancer. In addition, it has been hypothesized that adiponectin may exert carcinogenic effects through modulation of insulin sensitivity (Kelesidis et al. 2006). A limitation of this study is that information on insulin levels is not available. More studies to confirm and expand on these findings should be undertaken. Another limitation of this study was the availability of only a one-time blood measurement. However, previous studies showed that the stability and reliability of a one-time measure (as in this study) to be high (Pischon et al. 2003), and circulating levels do not appear to be affected significantly by either fasting or oral intake (Gavrila et al. 2003). Thus, any random error in the assays would tend to lead to underestimate of the true association. In conclusion, the findings of this study indicate an important role of adiponectin in the postmenopausal and ER-positive breast cancer risk. These associations were independent of measures of adiposity. More studies to confirm and expand on these findings should be undertaken, and mechanistic studies to fully elucidate the mechanisms underlying adiponectin’s effects should be pursued in future studies.
Acknowledgements This study was funded by grants from National Science Council (NSC 93-2320-B-016-016 and NSC 94-2314-B016-014), Department of Health (DOH 94-TD-F-113001), and Chi-Mei Fundation (95-CMNDMC01). The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.
References Althuis MD, Fergenbaum JH, Garcia-Closas M, Brinton LA, Madigan MP & Sherman ME 2004 Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiology, Biomarkers and Prevention 13 1558–1568.
www.endocrinology-journals.org
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K et al. 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochemical and Biophysical Research Communications 257 79–83. Bachelder RE, Wendt MA & Mercurio AM 2002 Vascular endothelial growth factor promotes breast carcinoma invasion in an autocrine manner by regulating the chemokine receptor CXCR4. Cancer Research 62 7203–7206. Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, Zhivotovsky B, Funahashi T & Cao Y 2004 Adiponectin-induced antiangiogenesis and antitumor activity involve caspase-mediated endothelial cell apoptosis. PNAS 101 2476–2481. Bulun SE, Mahendroo MS & Simpson ER 1994 Aromatase gene expression in adipose tissue: relationship to breast cancer. Journal of Steroid Biochemistry and Molecular Biology 49 319–326. van der Burg B, Rutteman GR, Blankenstein MA, de Laat SW & van Zoelen EJ 1988 Mitogenic stimulation of human breast cancer cells in a growth factor-defined medium: synergistic action of insulin and estrogen. Journal of Cell Physiology 134 101–108. Calle EE & Kaaks R 2004 Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Reviews. Cancer 4 579–591. Chandran M, Phillips SA, Ciaraldi T & Henry RR 2003 Adiponectin: more than just another fat cell hormone? Diabetes Care 26 2442–2450. Chen DC, Chung YF, Yeh YT, Chaung HC, Kuo FC, Fu OY, Chen HY, Hou MF & Yuan SS 2005 Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Letters 237 109–114. Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ, Retzlaff BM, Knopp RH, Brunzell JD & Kahn SE 2003 Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46 459–469. Dal Maso L, Augustin LS, Karalis A, Talamini R, Franceschi S, Trichopoulos D, Mantzoros CS & La Vecchia C 2004 Circulating adiponectin and endometrial cancer risk. Journal of Clinical Endocrinology and Metabolism 89 1160–1163. Fletcher O, Gibson L, Johnson N, Altmann DR, Holly JM, Ashworth A, Peto J & Silva Idos S 2005 Polymorphisms and circulating levels in the insulin-like growth factor system and risk of breast cancer: a systematic review. Cancer Epidemiology, Biomarkers and Prevention 14 2–19. Gavrila A, Chan JL, Yiannakouris N, Kontogianni M, Miller LC, Orlova C & Mantzoros CS 2003 Serum adiponectin levels are inversely associated with overall and central fat distribution but are not directly regulated by acute fasting or leptin administration in humans: cross-sectional and interventional studies. Journal of Clinical Endocrinology and Metabolism 88 4823–4831.
675
Y-F Tian, C-H Chu et al.: Adiposity, adiponectin, and breast cancer Harvie M, Hooper L & Howell AH 2003 Central obesity and breast cancer risk: a systematic review. Obesity Reviews 4 157–173. Haslam DW & James WP 2005 Obesity. Lancet 366 1197–1209. Huang Z, Willett WC, Colditz GA, Hunter DJ, Manson JE, Rosner B, Speizer FE & Hankinson SE 1999 Waist circumference, waist:hip ratio, and risk of breast cancer in the Nurses’ Health Study. American Journal of Epidemiology 150 1316–1324. Kaaks R 1996 Nutrition, hormones, and breast cancer: is insulin the missing link? Cancer Causes and Control 7 605–625. Kelesidis I, Kelesidis T & Mantzoros CS 2006 Adiponectin and cancer: a systematic review. British Journal of Cancer 94 1221–1225. Kirschner MA, Samojlik E, Drejka M, Szmal E, Schneider G & Ertel N 1990 Androgen-estrogen metabolism in women with upper body versus lower body obesity. Journal of Clinical Endocrinology and Metabolism 70 473–479. Ko¨rner A, Kratzsch J & Kiess W 2006 Effect of adiponectin on proliferation of breast cancer cells. Experimental and Clinical Endocrinology and Diabetes 114 S1 P03_043 Lahmann PH, Hoffmann K, Allen N, van Gils CH, Khaw KT, Tehard B, Berrino F, Tjonneland A, Bigaard J, Olsen A, Overvad K & Clavel-Chapelon F 2004 Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). International Journal of Cancer 111 762–771. Lai A, Sarcevic B, Prall OW & Sutherland RL 2001 Insulin/insulin-like growth factor-I and estrogen cooperate to stimulate cyclin E-Cdk2 activation and cell Cycle progression in MCF-7 breast cancer cells through differential regulation of cyclin E and p21(WAF1/Cip1). Journal of Biological Chemistry 276 25823–25833. Mantzoros C, Petridou E, Dessypris N, Chavelas C, Dalamaga M, Alexe DM, Papadiamantis Y, Markopoulos C, Spanos E, Chrousos G et al. 2004 Adiponectin and breast cancer risk. Journal of Clinical Endocrinology and Metabolism 89 1102–1107. Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA & Manson JE 2003 Type 2 diabetes and subsequent incidence of breast cancer in the Nurses’ Health Study. Diabetes Care 26 1752–1758. Milazzo G, Giorgino F, Damante G, Sung C, Stampfer MR, Vigneri R, Goldfine ID & Belfiore A 1992 Insulin receptor expression and function in human breast cancer cell lines. Cancer Research 52 3924–3930. Miyoshi Y, Funahashi T, Kihara S, Taguchi T, Tamaki Y, Matsuzawa Y & Noguchi S 2003 Association of serum adiponectin levels with breast cancer risk. Clinical Cancer Research 9 5699–5704. Modugno F, Kip KE, Cochrane B, Kuller L, Klug TL, Rohan TE, Chlebowski RT, Lasser N & Stefanick ML 2006 Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer. International Journal of Cancer 118 1292–1301.
676
Morimoto LM, White E, Chen Z, Chlebowski RT, Hays J, Kuller L, Lopez AM, Manson J, Margolis KL, Muti PC et al. 2002 Obesity, body size, and risk of postmenopausal breast cancer: the Women’s Health Initiative (United States). Cancer Causes and Control 13 741–751. Ng EH, Gao F, Ji CY, Ho GH & Soo KC 1997 Risk factors for breast carcinoma in Singaporean Chinese women: the role of central obesity. Cancer 80 725–731. Petridou E, Mantzoros C, Dessypris N, Koukoulomatis P, Addy C, Voulgaris Z, Chrousos G & Trichopoulos D 2003 Plasma adiponectin concentrations in relation to endometrial cancer: a case–control study in Greece. Journal of Clinical Endocrinology and Metabolism 88 993–997. Petridou E, Mantzoros CS, Dessypris N, Dikalioti SK & Trichopoulos D 2006 Adiponectin in relation to childhood myeloblastic leukaemia. British Journal of Cancer 94 156–160. Pfeiler GH, Treeck O, Neumeier M, Scha¨ffler A, Horn F, Buechler C & Ortmann O 2006 Effects of adiponectin on human breast cancer cells in vitro. German Medical Science. Pischon T, Hotamisligil GS & Rimm EB 2003 Adiponectin: stability in plasma over 36 h and within-person variation over 1 year. Clinical Chemistry 49 650–652. Potischman N, Swanson CA, Siiteri P & Hoover RN 1996 Reversal of relation between body mass and endogenous estrogen concentrations with menopausal status. Journal of National Cancer Institute 88 756–758. Retnakaran R, Hanley AJ, Connelly PW, Maguire G, Sermer M & Zinman B 2006 Low serum levels of high-molecular weight adiponectin in Indo-Asian women during pregnancy: evidence of ethnic variation in adiponectin isoform distribution. Diabetes Care 29 1377–1379. Rinaldi S, Key TJ, Peeters PH, Lahmann PH, Lukanova A, Dossus L, Biessy C, Vineis P, Sacerdote C, Berrino F et al. 2006 Anthropometric measures, endogenous sex steroids and breast cancer risk in postmenopausal women: a study within the EPIC cohort. International Journal of Cancer 118 2832–2839. Rose DP, Komninou D & Stephenson GD 2004 Obesity, adipocytokines, and insulin resistance in breast cancer. Obesity Reviews 5 153–165. Shu XO, Jin F, Dai Q, Shi JR, Potter JD, Brinton LA, Hebert JR, Ruan Z, Gao YT & Zheng W 2001 Association of body size and fat distribution with risk of breast cancer among Chinese women. International Journal of Cancer 94 449–455. Silteri PK 1987 Adipose tissue as a source of hormones. American Journal of Clinical Nutrition 45 277–282. Soliman PT, Wu D, Tortolero-Luna G, Schmeler KM, Slomovitz BM, Bray MS, Gershenson DM & Lu KH 2006 Association between adiponectin, insulin resistance, and endometrial cancer. Cancer 106 2376–2381. Stoll BA 2002 Upper abdominal obesity, insulin resistance and breast cancer risk. International Journal of Obesity and Related Metabolic Disorders 26 747–753. Tavassoli FA 2003 Pathology of the Breast. Stamford: Appleton & Lange.
www.endocrinology-journals.org
Endocrine-Related Cancer (2007) 14 669–677 Trujillo ME & Scherer PE 2005 Adiponectin: journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. Journal of Internal Medicine 257 167–175. Tworoger SS, Heather Eliassen A, Kelesidis T, Colditz GA, Willett WC, Mantzoros CS & Hankinson SE 2007 Plasma adiponectin concentrations and risk of incident breast cancer. Journal of Clinical Endocrinology and Metabolism 92 1510–1516. Wei EK, Giovannucci E, Fuchs CS, Willett WC & Mantzoros CS 2005 Low plasma adiponectin levels and risk of colorectal cancer in men: a prospective study. Journal of National Cancer Institute 97 1688–1694.
www.endocrinology-journals.org
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE & Tataranni PA 2001 Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. Journal of Clinical Endocrinology and Metabolism 86 1930–1935. Wolf I, Sadetzki S, Catane R, Karasik A & Kaufman B 2005 Diabetes mellitus and breast cancer. Lancet Oncology 6 103–111. Yager JD & Davidson NE 2006 Estrogen carcinogenesis in breast cancer. New England Journal of Medicine 354 270–282.
677
