Adiposity and breast, endometrial, and colorectal cancer risk in postmenopausal women: Quantification of the mediating effects of leptin, C‐reactive protein, fasting insulin, and estradiol

Abstract

Background Mechanisms underlying the adiposity–cancer relationship are incompletely understood. We quantified the mediating roles of C‐reactive protein (CRP), leptin, fasting insulin, and estradiol in the effect of adiposity on estrogen receptor (ER)‐positive breast, endometrial, and colorectal cancer risk in postmenopausal women. Methods We used a case–cohort study within the Women's Health Initiative Observational Study, analyzed as a cumulative sampling case–control study. The study included 188 breast cancer cases, 98 endometrial cancer cases, 193 colorectal cancer cases, and 285 controls. Interventional indirect and direct effects on the risk ratio (RR) scale were estimated using causal mediation analysis. Results For breast cancer, the total effect RR for BMI ≥30 versus ≥18.5–<25 kg/m2 was 1.87 (95%CI,1.11–3.13). The indirect effect RRs were 1.38 (0.79–2.33) through leptin and CRP, 1.58 (1.17–2.43) through insulin, and 1.11 (0.98–1.30) through estradiol. The direct effect RR was 0.82 (0.39–1.68). For endometrial cancer, the total effect RR was 2.12 (1.12–4.00). The indirect effect RRs were 1.72 (0.85–3.98) through leptin and CRP, 1.42 (0.96–2.26) through insulin, and 1.24 (1.03–1.65) through estradiol. The direct effect RR was 0.70 (0.23–2.04). For colorectal cancer, the total effect RR was 1.70 (1.03–2.79). The indirect effect RRs were 1.04 (0.61–1.72) through leptin and CRP, 1.36 (1.00–1.88) through insulin, and 1.02 (0.88–1.17) through estradiol. The direct effect RR was 1.16 (0.58–2.43). Conclusion Leptin, CRP, fasting insulin, and estradiol appear to mediate the effect of high BMI on cancer risk to different extents, with likely varying degrees of importance between cancers. These insights might be important in developing interventions to modify obesity‐associated cancer risk in postmenopausal women.

Bioinformatics Method Was Used to Analyze the Highly Expressed Gene FAM83A of Breast Cancer in Young Women

“…Numerical Library Research Pivot New Gene Indication Using Database and Human Protein Atlas (HPA) were used for the verification of key protein. Examination of the indication of the mRNA and egg white grades of the central gene between breast cancer tumor tissue and normal tissue was performed [ 27 ].…”

The impact of bariatric and metabolic surgery on cancer development

“…These effects are the same for sleeve gastrectomy and Y-Roux gastric bypass (59,60). Data from studies with a follow-up of at least ten years confirm that bariatric and metabolic surgery significantly also impacts the risk of cancer development in type 2 diabetes mellitus patients (36)(37)(38)54). Women with type 2 diabetes mellitus and an HbA1C ≥ 8% appear to have an increased risk of developing a tumor than men (35,36).…”

“…Obesity, often associated with impaired glucose hemostasis and insulin resistance, is reported to be connected to a higher activity of inflammatory cytokines such as tumor necrosis factor (TNF)α and interleukin (IL)-6 (27). Elevated levels of unbound insulin-like growth factor (IGF)-1 protein, for example, promote tumor growth by insulin and IGF-1 receptors (20, 21, 27), whereas leptin and adiponectin play another essential role in these molecular mechanisms (37). Glucagon-like peptide (GLP)-1 and its receptor have also been implicated in the insulin metabolism that plays a dominant role in cell and tumor growth (27,35).…”

“…Women with type 2 diabetes mellitus and an HbA1C ≥ 8% appear to have an increased risk of developing a tumor than men (35,36). This might be explained by the fact that endocrine interactions between the insulin signaling and the gonadal axis leading to increased estrogen levels are thus higher in premenopausal women than in men (37,38). Indirect mechanisms that lead to a risk reduction for cancer development include increased postprandial secretion of satiety hormones such as GLP-1, peptide YY (PYY), and oxyntomodulin (OXM) (52,53).…”

“…Indirect mechanisms that lead to a risk reduction for cancer development include increased postprandial secretion of satiety hormones such as GLP-1, peptide YY (PYY), and oxyntomodulin (OXM) (52,53). The postoperatively increased GLP-1 levels and their effect on insulin are discussed as a possible mediator of angiogenesis and cell growth (20-28, 30, [33][34][35][36][37]53). Accordingly, to these mechanisms, this effect is increased in insulin-dependent type 2 diabetes mellitus patients (31,32,34,(52)(53)(54)(55)(56)(57)62).…”