Journal Article

Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer

Wellberg, Elizabeth A., Johnson, Ginger, Jindal, Sonali, MacLean, Paul S., Corleto, Karen A., Obeid, Sarina, Higgins, Janine A., Anderson, Steven M., Checkley, L. Allyson, Schedin, Pepper J., Thor, Ann D., Giles, Erin D.

2022

Overview

Background Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. Methods We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. We tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. Results In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (i.e., BDNF, TNFα, FGF-2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1 in mammary adipose, and reduced phosphorylated FGFR indicating reduced FGF signaling in tumors. Conclusions Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multi-factorial, and that weight maintenance during the peri-/postmenopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adipocytes / Adipose tissue / Analysis / Animal models / Animals / Antibodies / Biomedical and Life Sciences / Biomedicine / Body weight loss / Brain-derived neurotrophic factor / Breast cancer / Breast Neoplasms - chemically induced / Breast Neoplasms - prevention & control / Cancer / Cancer interception / Cancer Research / Carcinogens / Cytokines / Diet / Female / Fibroblast growth factor 1 / Fibroblast growth factor 2 / Fibroblast growth factor receptors / Fibroblast growth factors / Gastrointestinal surgery / Growth factors / Humans / Hypotheses / Inflammation / Insulin / Insulin resistance / Laboratories / Macrophages / Menopause / Metabolism / Metastases / Mice / Mortality / Obesity / Obesity - complications / Obesity - metabolism / Oncology / Oncology, Experimental / Oophorectomy / Ovariectomy / Plasma / Post-menopause / Postmenopausal women / Postmenopause / Prevention / Rats / Research Article / Rodentia / Surgical Oncology / Tumor Burden / Tumor necrosis factor-α / Tumors / Weight control / Weight Gain / Weight loss maintenance / Womens health / Xenografts