Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women
Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations.
We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided.
Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk.
The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.
Available from: Randy Gaugler
- "High insulin and IGFs can directly promote tumor cell proliferation via insulin/IGF signaling pathway and thus are important risk factor for various cancers in over-weight individuals     and are known to be a powerful signaling system in the body that prohibits cells from committing suicide. Defect in this signaling system may allow insulin and IGFs to increase which may foster the development of colon, premenopausal breast, and aggressive prostate cancers    . Insulin resistance causes cells to become less sensitive to insulin effects in transporting glucose into cells but unlikely to reduce the growth promoting properties of insulin. "
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Lipid metabolism dysfunction leading to excess fat deposits (obesity) may cause tumor (cancer) development. Both obesity and cancer are the epicenter of important medical issues. Lipid metabolism and cell death/proliferation are controlled by biochemical and molecular pathways involving many proteins, and organelles; alteration in these pathways leads to fat accumulation or tumor growth. Mammalian Krüppel-like factors, KLFs play key roles in both lipid metabolism and tumor development.
Scope of review:
Substantial epidemiological and clinical studies have established strong association of obesity with a number of human cancers. However, we need more experimental verification to determine the exact role of this metabolic alteration in the context of tumor development. A clear understanding of molecules, pathways and the mechanisms involved in lipid metabolism and cell death/proliferation will have important implications in pathogenesis, and prevention of these diseases.
The regulatory role of KLFs, in both cell death/proliferation and lipid metabolism suggests a common regulation of both processes. This provides an excellent model for delivering a precise understanding of the mechanisms linking altered expression of KLFs to obesity and tumor development.
Currently, mouse and rats are the models of choice for investigating disease mechanisms and pharmacological therapies but a genetic model is needed for a thorough examination of KLF function in vivo during the development of an organism. The worm Caenorhabditis elegans is an ideal model to study the connectivity between lipid metabolism and cell death/proliferation.
Available from: Chengzhi Du
- "Among patients with mammary hyperplasia, some studies have reported increased levels of estrogen and estrogen receptors –. High levels of serum estrogen are similarly associated with higher incidence of breast cancer , , and more than 60% of human breast tumors are positive for ERα. ERα participates in a variety of different signaling pathways in mammary epithelial cells , and promotes cell proliferation mainly via its regulation of G1-S cell cycle progression , . "
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ABSTRACT: The Tongshu Capsule (TSC) is a prevalent form of traditional Chinese medicine widely used for its purported effects in treating mammary gland hyperplasia and inflammation. Though successful in several clinical studies, there is no clear evidence as to why TSC has a positive treatment effect, and little known about underlying mechanism that may account for it. In this study, we examined the effects of TSC and found that it has a comparatively strong growth inhibition on ERα positive breast cancer cells. TSC seems to cause G1 cell cycle arrest instead of apoptosis. Interestingly, TSC also down-regulated the expression of ERα and Cyclin D1. Consistently, TSC suppressed E2 mediated ERα downstream gene expression and cell proliferation in ERα positive breast cancer cell lines MCF7 and T47D. Depletion of ERα partially abolished the effects of TSC on the decrease of Cyclin D1 and cell viability. Our findings suggest that TSC may have therapeutic effects on ERα positive breast cancers and moreover that TSC may suppress breast epithelial cell proliferation by inhibiting the estrogen pathway.
Available from: Rafaela G. Feresin
- "Although the exact mechanisms underlying this observation are not fully understood, this protective effect could be attributed to increased mechanical load, imposed by a greater weight on weight-bearing bones as well as hormonal changes associated with obesity, for example, increased synthesis of estrogen and leptin by adipocytes. Higher levels of estrogen, known to suppress osteoclastic bone resorption and stimulate osteoblastic bone formation, have been found in serum of obese postmenopausal women when compared to their normal weight counterparts . This fact is attributed to an increased peripheral production of estrone through increased aromatization of androstenedione by aromatase in the white adipose tissue  . "
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ABSTRACT: Obesity and osteoporosis are two chronic conditions that have been increasing in prevalence. Despite prior data supporting the positive relationship between body weight and bone mineral density (BMD), recent findings show excess body weight to be detrimental to bone mass, strength, and quality. To evaluate whether obesity would further exacerbate the effects of ovariectomy on bone, we examined the tibiae and fourth lumbar (L4) vertebrae from leptin receptor-deficient female (íµí°¿íµí±íµí±íµí± íµí±íµí±/íµí±íµí±) Zucker rats and their heterozygous lean controls (íµí°¿íµí±íµí±íµí± íµí±íµí±/+) that were either sham-operated or ovariectomized (Ovx). BMD of L4 vertebra was measured using dual-energy X-ray absorptiometry, and microcomputed tomography was used to assess the microstructural properties of the tibiae. Ovariectomy significantly (íµí± < 0.001) decreased the BMD of L4 vertebrae in lean and obese Zucker rats. Lower trabecular number and greater trabecular separation (íµí± < 0.001) were also observed in the tibiae of lean-and obese-Ovx rats when compared to sham rats. However, only the obese-Ovx rats had lower trabecular thickness (Tb.Th) (íµí± < 0.005) than the other groups. These findings demonstrated that ovarian hormone deficiency adversely affected bone mass and quality in lean and obese rats while obesity only affected Tb.Th in Ovx-female Zucker rats.
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