02 Jul Links Between Breast Cancer and Obesity Studied
MedicalResearch.com Interview with
Sai-Ching Jim Yeung, MD, PhD, FACP
Professor of Medicine
The University of Texas MD Anderson Cancer Center
Department of Emergency Medicine
Department of Endocrine Neoplasia & Hormonal Disorders
Houston, Texas 77230-1402
MedicalResearch: What are the main findings of the study?
Dr. Yeung: We believe that this study has bridged a significant gap in knowledge between epidemiological data (the association of obesity and poor breast cancer prognosis) and biological mechanisms mediating the impact of obesity on cancer. This study provides an important mechanistic insight into the causal relationship between obesity and breast cancer growth.
- Direct evidence for the links between obesity-associated changes in the biological processes and hallmarks of cancer in human estrogen receptor-positive (ER+) breast cancer.
It is well known that obesity is associated epidemiologicaly with decreased survival in ER+ breast cancer patients. Although a body of experimental literature exists to suggest important roles for estrogen, insulin/IGF-1 and adipokine signaling and inflammation in the mechanisms mediating the impact of obesity on cancer, direct evidence for these mechanisms and their importance relative to one another is lacking in cancers from obese humans.
Functional transcriptomic analysis of a prospective observation cohort with treatment-naïve ER+ breast cancer samples identified the insulin/PI3K signaling and secretion of cytokines among the top biological processes involved. Many of the obesity-associated changes in biological processes can be linked to cancer hallmarks. Upstream regulator analysis identified estrogen (?-estradiol), insulin (INS1), insulin-like growth factor-1 (IGF1), and adipokines [vascular endothelial growth factor A (VEGFA), tissue necrosis factor (TNF), interleukin-6 (IL6), oncostatin-M (OSM), chemokine ligand 5 (CCL5), leptin (LEP), leukemia inhibitory factor (LIF), C-reactive protein (CRP), adiponectin (ADIPOQ), and interleukin-10 (IL10)] in mediating the impact of obesity on human ER+ breast cancer.
- Experimental evidence that obesity causes accelerated oncogene-driven ER+ breast cancer carcinogenesis.
While it is not possible to conduct a human experiment to prospectively examine the causal relationship between obesity and breast cancer, we created a transgenic mouse model with genetically induced obesity and oncogene-driven breast cancer. With this model we found strong in vivo evidence using both longitudinal experiments and cross-sectional experiments that obesity accelerated oncogene-driven breast carcinogenesis.
- Our mouse model phenocopied obese ER+ breast cancer patients and recapitulated transcriptomic changes associated with obesity in humans.
The human obesity phenotype is characterized by over consumption of food, insulin resistance, and increased estrogen level. The Ay/a genotype causes obesity in mice. These mice are obese without having to change the composition and fat content of the chow. Both the obese mice and the control lean mice were fed with the same chow, eliminating the influence of dietary composition on carcinogenesis. This obesity model has intact leptin signaling as opposed to other models such as those with ob/ob mutation or db/db mutation. This mouse model also recapitulated the human obesity endocrinology profile (high estrogen, fasting insulin and IGF-1 levels). The MMTV-TGF? transgene is causing the breast cancer formation. Therefore, the Ay/a model phenocopied many characteristics of human obesity.
Functional transcriptomic analysis similar to our analysis of the human breast cancer samples was performed on breast cancers from obese and lean control mice. Comparison of mouse data with human data showed that, although there were differences in specific mediators or the relative contribution by specific mediators involved, the major features of the obesity-induced functional changes of the transcriptomic landscape in human breast cancers were recapitulated in the mouse breast cancers. The similarity between the data from human and mouse breast cancers supports the extension of findings in our mouse model (i.e., obesity accelerated oncogene-driven breast carcinogenesis, and cancer growth of already transformed breast epithelial cells) to humans.
- Mature adipocytes stimulated breast cancer cell proliferation at least in part humorally obesity accelerated ER+ breast cancer growth after malignant transformation had already occurred.
An in vitro co-culture model revealed that adipocyte-secreted adipokines (e.g., TIMP-1) regulate adipocyte-induced breast cancer cell proliferation and invasion. Metformin suppress adipocytes-induced cell proliferation and adipocytes-secreted adipokines in vitro. We also investigate whether obesity can accelerate breast cancer cell proliferation, tumor formation and progression using an obese orthotopic-allograft model. This mouse model promoted cancer progression.
- Major role of the Akt/mTOR pathway in obesity-induced breast carcinogenesis and tumor progression. Metformin and everolimus can suppress obesity-induced adipokines secretion and breast tumor formation and growth.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Yeung: Adipokine secretion and Akt/mTOR activation play important roles in obesity-accelerated breast cancer aggressiveness in addition to hyperinsulinemia, estrogen signaling, and inflammation. Metformin and everolimus have potential for therapeutic interventions of ER+ breast cancer patients with obesity.
Weight loss presumably should slow down ER+ breast cancer progression in overweight and obese patients.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Yeung: Postmenopausal patients with metastatic ER+ breast cancer may be treated with exemestane and everolimus. Overweight and obese patients often develop hyperglycemia with everolimus. Metformin may improve hyperglycemia by improving insulin resistance. The combination of everolimus and metformin may be beneficial for overweight and obese patients with advanced ER+ breast cancer. Future research should include a prospective clinical trial to evaluate the efficacy of metformin and everolimus in overweight and obese ER+ breast cancer patients.
Effects of Obesity on Transcriptomic Changes and Cancer Hallmarks in Estrogen Receptor–Positive Breast Cancer
Enrique Fuentes-Mattei, Guermarie Velazquez-Torres, Liem Phan, Fanmao Zhang, Ping-Chieh Chou, Ji-Hyun Shin, Hyun Ho Choi, Jiun-Sheng Chen, Ruiying Zhao, Jian Chen, Chris Gully, Colin Carlock, Yuan Qi, Ya Zhang, Yun Wu, Francisco J. Esteva, Yongde Luo, Wallace L. McKeehan, Joe Ensor, Gabriel N. Hortobagyi, Lajos Pusztai, W. Fraser Symmans, Mong-Hong Lee, and Sai-Ching Jim Yeung
JNCI J Natl Cancer Inst (2014)106 (7):dju158 doi:10.1093/jnci/dju158