Adipose Tissue—Breast Cancer Crosstalk Leads to Increased Tumor Lipogenesis Associated with Enhanced Tumor Growth

Abstract

We sought to identify therapeutic targets for breast cancer by investigating the metabolic symbiosis between breast cancer and adipose tissue. To this end, we compared orthotopic E0771 breast cancer tumors that were in direct contact with adipose tissue with ectopic E0771 tumors in mice. Orthotopic tumors grew faster and displayed increased de novo lipogenesis compared to ectopic tumors. Adipocytes release large amounts of lactate, and we found that both lactate pretreatment and adipose tissue co-culture augmented de novo lipogenesis in E0771 cells. Continuous treatment with the selective FASN inhibitor Fasnall dose-dependently decreased the E0771 viability in vitro. However, daily Fasnall injections were effective only in 50% of the tumors, while the other 50% displayed accelerated growth. These opposing effects of Fasnall in vivo was recapitulated in vitro; intermittent Fasnall treatment increased the E0771 viability at lower concentrations and suppressed the viability at higher concentrations. In conclusion, our data suggest that adipose tissue enhances tumor growth by stimulating lipogenesis. However, targeting lipogenesis alone can be deleterious. To circumvent the tumor’s ability to adapt to treatment, we therefore believe that it is necessary to apply an aggressive treatment, preferably targeting several metabolic pathways simultaneously, together with conventional therapy.

C1QTNF3 is Upregulated During Subcutaneous Adipose Tissue Remodeling and Stimulates Macrophage Chemotaxis and M1-Like Polarization

“…As expected, the HFD-fed mice developed obesity and exhibited almost three times larger tumors than the chow-fed lean controls ( Figures 1A, B ) . This difference in E0771 tumor progression between lean and obese mice agrees with previous studies ( 18 , 40 ). The global gene expression profiles of cancer-associated and control IWAT were compared using RNA-sequencing.…”

“…However, contrary to this idea, we did not detect major changes in the percentage or polarization of tumor-associated macrophages between lean and HFD-induced obese mice. Moreover, our recent work shows that interactions between tumor and adjacent adipose tissue stimulate tumor growth to a similar degree in lean and obese mice ( 18 ), suggesting that the increased E0771 tumor growth in the obese mice primarily is due to systemic metabolic and/or endocrine alteration. Thus, we interpret the enhanced macrophage accumulation along with many of the enhanced transcriptional changes in obese tumor-associated IWAT rather as a consequence from the faster growing tumors than the cause.…”

“…Paracrine crosstalk between adipose tissue and cancer cells has been shown to enhance tumor growth ( 13 – 18 ), and the mechanical pressure from a growing tumor will also trigger substantial tissue remodeling in adjacent adipose tissue. To identify new adipose tissue-derived factors potentially important in subcutaneous adipose tissue remodeling and/or tumor progression, we compared the global gene expression profiles of breast cancer-associated and control inguinal/mammary white adipose tissue (IWAT) from lean and high fat diet (HFD)-induced obese female C57Bl/6 mice.…”

Diets Differently Regulate Tumorigenesis in Young E0771 Syngeneic Breast Cancer Mouse Model

“…Diets mainly rich in fat increase body fat mass and alter the composition and physiology of adipose tissue, including at the breast stromal site. Many studies have explored the chronic effects of HFD-induced obesity on tumorigenesis and metastasis in the pathogenesis of BC using various mouse mammary tumor models, such as E0771 and MMTV-PyMT [ 17 , 18 ]. Earlier studies have demonstrated that feeding mice a HFD for 12–16 weeks induces not just obesity but also increases pro-inflammatory cytokines in the mammary fat pad [ 16 , 17 ], tumor lipogenesis [ 18 ], and estrogen levels [ 19 ], which are associated with high risk of tumor progression and metastasis in BC.…”

“…Diet composition may play a major role in determining body fat mass and regulating metabolic or nutritional stress. The majority of the previous studies were mainly focused on studying the effect of obesity-induced inflammatory signaling and changes in the estrogen levels on the pathogenesis of BC using mature adult mice (>12 weeks old) treated with HFD for prolonged periods (12–16 weeks) [ 16 , 17 , 18 , 19 ]. However, the change in diet composition even for a short time (4–6 weeks) in growing adolescent mice may have an impact on mammary fat pad composition, development of mammary glands, and susceptibility to tumorigenesis.…”