Journal
BREAST CANCER RESEARCH
Volume 24, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13058-022-01535-x
Keywords
Diet; Obesity; Animal models; Cancer interception; Inflammation; Cytokines; Tumor microenvironment; Menopause; Postmenopausal; Visceral fat; Growth factors
Categories
Funding
- NIH [NCI R00 CA169430, R01 CA164166, R01 CA241156, R25CA203650]
- Cancer Prevention Research Institute of Texas
- Nutrition and Obesity Research Center Support grant NIH [P30 DK48520]
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Preventing weight gain after ovariectomy can decrease the development and growth of obesity-associated breast tumors, reduce visceral fat accumulation and insulin resistance. It also decreases the levels of tumor-promoting growth factors and inflammatory cytokines, and reduces the expression of tumor-promoting factors in mammary adipose tissue.
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, TNF alpha, 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.
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