Abstract
Obesity is clearly associated with an increased risk of breast cancer in postmenopausal women. The purpose was to determine if obesity alters the adipocyte adipokine secretion profile, thereby altering the adipose-dependent paracrine/endocrine growth microenvironment surrounding breast cancer cells (MCF7). Additionally, we determined whether resveratrol (RSV) supplementation can counteract any obesity-dependent effects on breast cancer tumor growth microenvironment. Obese ZDF rats received standard chow diet or diet supplemented with 200 mg/kg body weight RSV. Chow-fed Zucker rats served as lean controls. After 6 weeks, conditioned media (CM) prepared from inguinal subcutaneous adipose tissue (scAT) was added to MCF7 cells for 24 hrs. Experiments were also conducted using purified isolated adipocytes to determine whether any endocrine effects could be attributed specifically to the adipocyte component of adipose tissue. scAT from ZDF rats promoted cell cycle entry in MCF7 cells which was counteracted by RSV supplementation. RSV-CM had a higher ratio of ADIPO:LEP compared to ZDF-CM. This altered composition of the CM led to increased levels of pAMPKT172, p27, p27T198 and AdipoR1 while decreasing pAktT308 in MCF7 cells grown in RSV-CM compared to ZDF-CM. RSV-CM increased number of cells in G0/G1 and decreased cells in S-phase compared to ZDF-CM. Co-culture experiments revealed that these obesity-dependent effects were driven by the adipocyte component of the adipose tissue. Obesity decreased the ratio of adiponectin:leptin secreted by adipocytes, altering the adipose-dependent growth microenvironment resulting in increased breast cancer cell proliferation. Supplementation with RSV reversed these adipose-dependent effects suggesting a potential for RSV as a nutritional supplementation to improve breast cancer treatment in obese patients.
Highlights
Breast cancer is a dynamic, multi-factorial and inherently complex disease
As subcutaneous adipose tissue (scAT) from “obese” ZDF rats elicited decreases in pAMPKT172 and increases in pAktT308 in MCF7 cells compared to scAT from lean animals in both co-culture (Fig 3) and conditioned media (CM) experiments (Fig 5)
The downstream cell cycle effects of this AMPK/AKT antagonism was manifested by decreases in the levels of p27, p27T198 and AdipoR1 and increases in cyclin E, indicating increased proliferation, which was confirmed using FACS analyses
Summary
The tumor growth environment within each individual patient is much more stable and uniform, since the majority of factors within this environment are originate from predictable determinants of patient physiology. Targeting this growth microenvironment therapeutically may elicit more predictive treatment outcomes across patients and over a broader range of tumor types. Since the vast majority of tumors are surrounded by adipocytes and adipocytes serve as an active endocrine tissue, there may exist direct effects of adipose on tumor growth [1,2] making adipocytes, and adipose as a whole, viable targets for novel cancer therapeutic strategies. There is a clear connection between adiposity and breast cancer emphasizing the existence of a role of adipose tissue in regulating cancer progression
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