Effect of Obesity-associated Iron Dysregulation on Breast Cancer Risk in Postmenopausal Women
thesisposted on 2015-02-27, 00:00 authored by Puja Agarwal
Background: Obesity is an established risk factor for postmenopausal breast cancer and also induces iron dysregulation via elevated hepcidin (hepatic peptide hormone). Hepcidin degrades ferroportin (FPN1-only known iron exporter) and traps iron that enhances carcinogenesis within the cell. Breast tumors with high hepcidin and low FPN1 have poor prognosis. The purpose of this study was to determine if systemic hepcidin explains established obesity enhancing risk of postmenopausal breast cancer and to discern the difference between iron accumulation and FPN1 expression within the breast tissues by disease status and obesity among them. Methods: A nested case (n=44)-control (n=44) study was conducted from a prospective cohort of women seeking breast biopsies. Newly diagnosed cases and controls were stratified by obesity status (BMI > 30 & < 30) and blood samples, anthropometric and baseline information were collected prior to biopsy. Plasma was analyzed for CRP, IL-6, leptin, adiponectin, estradiol, sTFR and hepcidin. Breast tissues (IDC (cases) and benign (controls)) were assessed for iron (Perls’ staining) and FPN1 (IHC). Results: Hepcidin (p=0.02) along with other obesity related factors for breast cancer (CRP, IL-6, leptin and estrogen; all p values ≤ 0.05) significantly differed with obesity status among the controls. Postmenopausal women with elevated hepcidin (>=152 ng/ml) had four times higher risk for breast cancer compared to those with lower levels (<152 ng/ml). Cases had similar sTFR but trended higher plasma hepcidin (p=0.1), iron accumulation (p=0.05) and decreased FPN1 expression (p=0.05) in their breast tissues’ macrophages compared to controls. Within cases, obese women had bigger tumors (p=0.02) and less iron accumulated in the macrophages (p=0.03). Conclusion: Influence of obesity on hepcidin reported in premenopausal women also occurs in postmenopausal women. Hepcidin level is associated with breast cancer and may represent a novel mechanism to explain the link between obesity and breast cancer. Our findings of diminished FPN1 coupled with increased iron accumulation in the macrophages surrounding the tumor suggest these cells serve as storage site for intracellular iron required for tumor growth. Further, we speculate decreased iron in the macrophages of obese women’s larger tumors reflect an adaptation for increased iron acquisition for disease advancement.