Impact Of Estrogen On The Relationship Between Obesity And Renal Cell Carcinoma Risk In Women

Objective: We conducted a multicenter case-control study to explore the role of estrogen as a potential modifier of the relationship between obesity and renal cell carcinoma(RCC)risk in women.Estrogen receptor-?(ER-?)and insulin-like growth factor(IGF)-1 receptor(IGF-1R)expression levels were detected in RCC tissues to investigate the possible mechanism.Methods: This retrospective study included 445 female RCC patients recruited from five regional medical centers who were pathologically confirmed by either renal surgery or core biopsy.Age-matched controls were enrolled from cancer-free females.Data on age,height,weight,waist circumference(WC),history of hypertension and diabetes,menstrual status,use of hormone replacement therapy(HRT),histological subtype,stage at diagnosis,and Fuhrman grade were collected from medical records.Continuous variables were expressed as mean � standard deviation and were compared between groups by using Student's t-tests.Categorical variables were expressed as frequencies and percentages and were compared using ?2 tests.Unconditional logistic regression analysis was used to estimate odds ratios(ORs)and 95% confidence intervals(CIs).ER-?and IGF-1R expression levels were detected in RCC tissues by immunohistochemistry(IHC).Results:(1)There was no significant difference between cases and controls in terms of age,menopause,or use of hormone replacement therapy(HRT).However,cases were more likely to be overweight(?25 kg/m~2),have a history of hypertension or diabetes,and have a larger waist circumference(WC).Clear cell RCC accounted for 81.80% of all cases.Fuhrman grades I,II,?,and ? were observed in 22,201,128,and 23 patients,respectively.Information on Fuhrman grade was lacking for 71 patients.Estrogenpositive women showed a significant positive association between overweight and RCC risk.Univariate and multivariate logistic regression models showed that overweight women with estrogen-positive status had an increased risk of RCC(OR: 1.67,95%CI: 1.01�2.76)after adjusting for potential confounders,while no such positive association was observed among the subjects as a whole.Regarding WC,women in quantiles 3 and 4 were at increased risk of RCC compared with women in quantile 1(quantile 3,OR: 1.64,95%CI: 1.12�2.39;quantile 4,OR: 1.57,95%CI: 1.07� 2.30).In addition,there was a positive association between WC and RCC risk in estrogen-positive women(quantile 3,OR: 2.00,95%CI: 1.09�3.66;quantile 4,OR: 2.54,95%CI: 1.28�5.03)(2)We determined the protein expression levels of ER-? and IGF-1R in 93 cc RCC specimens from female patients immunohistochemically.As expected,estrogen-negative patients were older than estrogen-positive ones.There were also more patients with hypertension in the estrogen-negative compared with the estrogen-positive group.Fuhrman grade ?+? was more common in estrogen-positive patients.However,there was no significant difference between the groups in relation to diabetes or clinical stage.IHC staining detected IGF-1R expression in 78.49%(73/93)of cc RCC specimens and ER-? in 22.58%(21/93)of specimens.IGF-1R expression levels were higher in estrogenpositive compared with estrogen-negative ones(p=0.015),but there was no significant difference in ER-? expression levels between the two groups.Conclusions: These results suggest that estrogen plays an important role in RCC etiology and may modify the association between obesity and RCC risk in women.We hypothesize that estrogen may up-regulate IGF-1R and potentiate the deleterious effects of obesity-related elevations of insulin and IGFs.