Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer
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 ha...
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-022-01535-x |
| _version_ | 1811334662455296000 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Elizabeth A. Wellberg |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T17:11:25Z |
| format | Article |
| id | doaj.art-fe059f40f7664debab0869772fb8b494 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-04-13T17:11:25Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-fe059f40f7664debab0869772fb8b4942022-12-22T02:38:16ZengBMCBreast Cancer Research1465-542X2022-06-0124111310.1186/s13058-022-01535-xPreventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancerElizabeth A. Wellberg0Karen A. Corleto1L. Allyson Checkley2Sonali Jindal3Ginger Johnson4Janine A. Higgins5Sarina Obeid6Steven M. Anderson7Ann D. Thor8Pepper J. Schedin9Paul S. MacLean10Erin D. Giles11Department of Pathology, Harold Hamm Diabetes Center, and Stephenson Cancer Center, University of Oklahoma Health Sciences CenterDepartment of Nutrition, Texas A&M UniversityDivisions of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical CampusDepartment of Cell, Developmental and Cancer Biology, Oregon Health & Science UniversityDivisions of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical CampusDepartment of Pediatrics, Endocrinology Section, University of Colorado Anschutz Medical CampusDepartment of Nutrition, Texas A&M UniversityDepartment of Pathology, University of Colorado Anschutz Medical CampusDepartment of Pathology, University of Colorado Anschutz Medical CampusDepartment of Cell, Developmental and Cancer Biology, Oregon Health & Science UniversityDivisions of Endocrinology, Metabolism, and Diabetes, University of Colorado Anschutz Medical CampusSchool of Kinesiology, University of MichiganAbstract 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.https://doi.org/10.1186/s13058-022-01535-xDietObesityAnimal modelsCancer interceptionInflammationCytokines |
| spellingShingle | 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 Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer Breast Cancer Research Diet Obesity Animal models Cancer interception Inflammation Cytokines |
| title | Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer |
| title_full | Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer |
| title_fullStr | Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer |
| title_full_unstemmed | Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer |
| title_short | Preventing ovariectomy-induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer |
| title_sort | preventing ovariectomy induced weight gain decreases tumor burden in rodent models of obesity and postmenopausal breast cancer |
| topic | Diet Obesity Animal models Cancer interception Inflammation Cytokines |
| url | https://doi.org/10.1186/s13058-022-01535-x |
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