Impact of obesity on breast cancer recurrence and minimal residual disease

Autor: Aaron Solomon, Dhruv K. Pant, Fei Shen, Tien Chi Pan, George K. Belka, Kathryn H. Schmitz, Samyukta Mahendra, Christopher J. Sterner, Jun Y. Lee, Lauren Vaught, Lewis A. Chodosh, Javier Peraza, Brett L. Ecker
Rok vydání: 2019
Předmět:
medicine.medical_specialty
Neoplasm
Residual
Receptor
ErbB-2
Datasets as Topic
Mice
Obese
Breast Neoplasms
Mice
Transgenic
Diet
High-Fat
lcsh:RC254-282
Body fat percentage
Disease-Free Survival
Body Mass Index
Increased body fat percentage
Impaired glucose tolerance
03 medical and health sciences
Breast cancer
0302 clinical medicine
Recurrence
Cell Line
Tumor
Internal medicine
medicine
Hyperinsulinemia
Animals
Humans
Obesity
2. Zero hunger
Adiponectin
business.industry
Body Weight
Mammary Neoplasms
Experimental
food and beverages
nutritional and metabolic diseases
Tumor dormancy
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Survival Analysis
Minimal residual disease
3. Good health
High-fat diet
Endocrinology
030220 oncology & carcinogenesis
Female
Resistin
Neoplasm Recurrence
Local
business
Research Article
Zdroj: Breast Cancer Research, Vol 21, Iss 1, Pp 1-16 (2019)
Breast Cancer Research : BCR
ISSN: 1465-542X
DOI: 10.1186/s13058-018-1087-7
Popis: Background Obesity is associated with an increased risk of breast cancer recurrence and cancer death. Recurrent cancers arise from the pool of residual tumor cells, or minimal residual disease (MRD), that survives primary treatment and persists in the host. Whether the association of obesity with recurrence risk is causal is unknown, and the impact of obesity on MRD and breast cancer recurrence has not been reported in humans or in animal models. Methods Doxycycline-inducible primary mammary tumors were generated in intact MMTV-rtTA;TetO-HER2/neu (MTB/TAN) mice or orthotopic recipients fed a high-fat diet (HFD; 60% kcal from fat) or a control low-fat diet (LFD; 10% kcal from fat). Following oncogene downregulation and tumor regression, mice were followed for clinical recurrence. Body weight was measured twice weekly and used to segregate HFD mice into obese (i.e., responders) and lean (i.e., nonresponders) study arms, and obesity was correlated with body fat percentage, glucose tolerance (measured using intraperitoneal glucose tolerance tests), serum biomarkers (measured by enzyme-linked immunosorbent assay), and tissue transcriptomics (assessed by RNA sequencing). MRD was quantified by droplet digital PCR. Results HFD-Obese mice weighed significantly more than HFD-Lean and LFD control mice (p < 0.001) and had increased body fat percentage (p < 0.001). Obese mice exhibited fasting hyperglycemia, hyperinsulinemia, and impaired glucose tolerance, as well as decreased serum levels of adiponectin and increased levels of leptin, resistin, and insulin-like growth factor 1. Tumor recurrence was accelerated in HFD-Obese mice compared with HFD-Lean and LFD control mice (median relapse-free survival 53.0 days vs. 87.0 days vs. 80.0 days, log-rank p < 0.001; HFD-Obese compared with HFD-Lean HR 2.52, 95% CI 1.52–4.16; HFD-Obese compared with LFD HR 2.27, 95% CI 1.42–3.63). HFD-Obese mice harbored a significantly greater number of residual tumor cells than HFD-Lean and LFD mice (12,550 ± 991 vs. 7339 ± 2182 vs. 4793 ± 1618 cells, p < 0.001). Conclusion These studies provide a genetically engineered mouse model for study of the association of diet-induced obesity with breast cancer recurrence. They demonstrate that this model recapitulates physiological changes characteristic of obese patients, establish that the association between obesity and recurrence risk is causal in nature, and suggest that obesity is associated with the increased survival and persistence of residual tumor cells. Electronic supplementary material The online version of this article (10.1186/s13058-018-1087-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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