The worldwide prevalence of overweight and obesity has tripled since 1975. In the United States, the percentage of adults who are obese exceeds 42.5%. Individuals with obesity often display multiple metabolic perturbations, such as insulin resistance and persistent inflammation, which can suppress the immune system. These alterations in homeostatic mechanisms underlie the clinical parameters of metabolic syndrome, an established risk factor for many cancers, including breast cancer. Within the growth-promoting, proinflammatory milieu of the obese state, crosstalk between adipocytes, immune cells and breast epithelial cells occurs via obesity-associated hormones, angiogenic factors, cytokines, and other mediators that can enhance breast cancer risk and/or progression. This review synthesizes evidence on the biological mechanisms underlying obesity-breast cancer links, with emphasis on emerging mechanism-based interventions in the context of nutrition, using modifiable elements of diet alone or paired with physical activity, to reduce the burden of obesity on breast cancer.
Background: Defects in primary cilium can lead to a group of disorders termed ciliopathies, with links to both obesity and cancer. Obesity causes inflammation and downregulates anti-tumor immunity generating a protumor microenvironment and increases the risk of breast cancer (BC) development and metastasis. Also, obesity affects cilium length, which could disrupt the essential role of the cilium in detecting extracellular cues, coordinating cell signaling responses, and regulating cell fate and mitochondrial function. However, there is a gap in understanding the effects of obesity on ciliogenesis in cancer cells and in regard to the impact of cilium length and localization on mitochondrial function of tumor cells. We therefore sought to elucidate the impact of obesity on the presence, localization, and function of primary cilium, using murine models of triple-negative breast cancer (TNBC). Methods: We generated mammary tumors by orthotopic transplantation of murine metM-Wntlung or E0771 TNBC cells, and evaluated the impact of obesity on ciliary specific gene sets in tumors using GSEA analysis. We also tested the abundance of cilium in tumor sections using immunofluorescence. Additionally, we developed metM-Wntlung and E0771 expressing the ciliary transmembrane protein Smo fluorescently tagged to pHluorin. Using these cells, we performed in vitro studies to investigate the length and cellular localization of the cilium in cancer cells in 3 compartments; intracellular (in), intermediate, or extracellular (out). Results: Our GSEA analysis results indicated significant upregulation of 18/19 ciliary gene sets in metM-Wntlung mammary tumors from obese mice and 19/19 ciliary gene sets in E0771 mammary tumors from obese mice compared to the corresponding tumors developed in non-obese mice. Ongoing leading-edge analysis will determine the genes driving the enrichment of ciliary-related gene sets in tumors of obese mice. Immunofluorescence analysis showed a significant number of ciliated cells in tumor sections of obese mice and in cultured cells expressing pHluorin-Smo. Ongoing studies will reveal the specific cellular localization of the cilium on cancer cells and the effects on mitochondrial function. Our research is establishing a proof-of-concept that mammary cancer cells express cilium and will elucidate key mechanistic details related to the role of the primary cilium in the crosstalk between obesity and cancer metabolism. This research is supported by R35CA197627 (SDH), AICR Marylin Gentry Fellowship (XBM). Citation Format: Ximena Bustamante-Marin, Jenna L. Merlino, Emma J. Grindstaff, Michael F. Coleman, Erika Rezeli, Kristina K. Camp, Laura Smith, Stephen D. Hursting. Role of the primary cilium in the crosstalk between obesity and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2388.
Calorie restriction (CR) has an antitumorigenic effect against triple-negative breast cancer (TNBC). A key mitogenic pathway modulated by CR involves insulin-like growth factor (IGF)-1, which plays a central role in local and systemic growth and cell survival by activating the PI3K/AKT/mTOR pathway downstream of the IGF-1 receptor (IGF-1R). Although multiple miRNAs that target components of the IGF-1 signaling pathway have been identified, the impact of CR on IGF-1-related miRNA expression has not been addressed. We hypothesize that CR-induced decreases in TNBC development and progression involve miRNA's regulating IGF-1 signaling, we used C3(1)/SV40 T-antigen (C3-TAg) mice (a TNBC model), a C3-Tag progression series of cell lines (M28, M6, and M6C), and human TNBC cell line (MDA-MB-231). The expression of miRNAs previously reported to target components of the IGF-1 and/or mTOR pathways was evaluated by real-time PCR. Hormone levels were measured using the mouse Luminex Screening Assay. To mimic CR in vitro, and to test the effects of miRNA manipulation, the C3-Tag series of TNBC cell lines were treated (separately and in combination) with serum restriction, BMS754807 (inhibitor of IGF1-R), and various levels of recombinant IGF-1 as well as manipulated levels of miRNA's associated with IGF-1/mTOR signaling. We also conducted in silico analysis using Metabric, TCGA, TargetScan, and miRTarBase data sets to identify genes and pathways associated with specific miRNAs expression related to the PI3K/Akt/mTOR pathway. Our results confirm that CR maintains lower body weight, reduces circulating levels of IGF-1, and slows spontaneous TNBC development and progression in mice. CR also significantly increased the expression of miR-15b and miR-486. In vitro studies showed miR-15b and miR-486 expression decreased with increasing tumorigenicity of the C3-tag series of TNBC progression. Treatment of mouse and human TNBC cells with low IGF-1 induced miR-15b expression and inhibited proliferation. Moreover, miR-15b overexpression inhibited cell proliferation and decreased IGF-1R expression (mRNA and protein). Consistent with these results, the in silico analysis shows that the amplification of miR-15b correlates with downregulation of pathways involved in tumor growth and IGF1-R signaling. Together these findings suggest that reduced circulating IGF-1 levels in response to CR leads to the upregulation of miR-15b, which correspondingly targets and downregulates IGF-1R, both at the mRNA and protein levels. This combination of reduced IGF-1 ligand and miR-15b-induced IGF-1R downregulation contributes to the potent anticancer effects of CR and reveals potential targets for pharmacologically mimicking those effects. This research is supported by R35CA197627. Citation Format: Ximena Minerva Bustamante-Marin, Kaylyn L. Devlin, Om Dave, Jenna L. Merlino, Shannon B. McDonell, Michael F. Coleman, Stephen D. Hursting. Anticancer effects of calorie restriction in a murine C3-TAg model of triple-negative breast cancer: the role of miR-15b [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2357.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.