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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number42
JournalBreast Cancer Research
Volume24
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • Animal models
  • Cancer interception
  • Cytokines
  • Diet
  • Growth factors
  • Inflammation
  • Menopause
  • Obesity
  • Postmenopausal
  • Tumor microenvironment
  • Visceral fat

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer'. Together they form a unique fingerprint.

Cite this