Prevalence of obesity has steadily increased over the past three decades both in the United States and worldwide. Recent studies have shown the role of dietary polyphenols in the prevention of obesity and obesity-related chronic diseases. Here we evaluated the impact of commonly consumed polyphenols, including green tea catechins and epigallocatechin gallates, resveratrol, and curcumin, on obesity and obesity-related-inflammation. Cellular studies demonstrated that these dietary polyphenols reduce viability of adipocytes and proliferation of preadipocytes, suppress adipocyte differentiation and triglyceride accumulation, stimulate lipolysis and fatty acid β-oxidation, and reduce inflammation. Concomitantly, the polyphenols modulate signaling pathways including the AMP-activated protein kinase, peroxisome proliferator activated receptor γ, CCAAT/enhancer binding protein α, PPAR gamma activator 1-alpha, sirtuin 1, sterol regulatory element binding protein-1c, uncoupling proteins 1 and 2, and nuclear factor kappa B that regulate adipogenesis, antioxidant and anti-inflammatory responses. Animal studies strongly suggest that commonly consumed polyphenols described in this review have a pronounced effect on obesity as shown by lower body weight, fat mass, and triglycerides through enhancing energy expenditure and fat utilization, and modulating glucose hemostasis. Limited human studies have been conducted in this area, and are inconsistent about the anti-obesity impact of dietary polyphenols, probably due to the various study designs and lengths, variation among subjects (age, gender, ethnicity), chemical forms of the dietary polyphenols used and confounding factors such as other weight reducing agents. Future randomized controlled trials are warranted to reconcile the discrepancies between preclinical efficacies and inconclusive clinic outcomes of these polyphenols.

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Breast cancer (BrCa) relies on specific microRNAs to drive disease progression. Oncogenic miR-21 is upregulated in many cancers, including BrCa, and is associated with poor survival and treatment resistance. We sought to determine the role of miR-21 in BrCa tumor initiation, progression and treatment response. In a triple-negative BrCa model, radiation exposure increased miR-21 in both primary tumor and metastases. In vitro, miR-21 knockdown decreased survival in all BrCa subtypes in the presence of radiation. The role of miR-21 in BrCa initiation was evaluated by implanting wild-type miR-21 BrCa cells into genetically engineered mouse models where miR-21 was intact, heterozygous or globally ablated. Tumors were unable to grow in the mammary fat pads of miR-21−/− mice, and grew in ~50% of miR-21+/− and 100% in miR-21+/+ mice. The contribution of miR-21 to progression and metastases was tested by crossing miR-21−/− mice with mice that spontaneously develop BrCa. The global ablation of miR-21 significantly decreased the tumorigenesis and metastases of BrCa, while sensitizing tumors to radio- and chemotherapeutic agents via Fas/FasL-dependent apoptosis. Therefore, targeting miR-21 alone or in combination with various radio or cytotoxic therapies may represent novel and efficacious therapeutic modalities for the future treatment of BrCa patients.

Background: Metastatic cancer is incurable and understanding the molecular underpinnings is crucial to improving survival for our patients. The IGF-1/Akt signaling pathway is often impaired in cancer leading to its progression and metastases. Diet modification is known to alter the IGF-1/Akt pathway and affect the expression of microRNA involved in tumor initiation, growth and metastases. Liver metastases are one of the most common type of metastases in breast and colon cancer. In the present study, we looked at the effect of diet modification on the expression of microRNA in normal liver and liver with breast cancer metastases using in vivo model. Methodology: 6-month-old C57BL/6 J mice were put on either an ad libitum (AL) diet, or 40% calorie restricted (CR) diet or were fasted for 24 h (FA) before sacrifice. MicroRNA array analysis, western blot and qRT-PCR were performed using liver tissue to compare the treatment groups. A breast cancer model was also used to study the changes in microRNA expression in liver of a group of BALB/c mice orthotopically injected with 4 T1 cells in the mammary fat pad, put on either an AL or 30% CR diet. Liver and primary tumor tissues were used to perform qRT-PCR to compare the treatment groups. Results: MicroRNA array analysis showed significant changes in miRNA expression in both CR and FA conditions in normal liver. Expression of miR-29 and miR-30 family members was increased in both CR and FA. Western blot analysis of the normal liver tissue showed that CR and FA downregulated the IGF-1/Akt pathway and qRT-PCR showed that the expression of miR-29b, miR-29c, miR-30a and miR-30b were increased with CR and FA. Liver tissue collected from mice in the breast cancer model showed an increase in expression of miR-29b, miR-29c and miR-30b while tumor tissue showed increased expression of miR-29c, miR-30a and miR-30b. Discussion: Members of the miR-29 family are known to target and suppress IGF-1, while members of the miR-30 family are known to target and suppress both IGF-1 and IGF-1R. In the present study, we observe that calorie restriction increased the expression of miR-29 and miR-30 in both the normal liver as well as the liver with breast cancer metastases. These findings suggest that dietary alterations may play a role in the treatment of liver metastasis, which should be evaluated further.

BackgroundType 2 diabetes is often linked with impaired proximal insulin signaling. Hence, a therapeutic agent that enhances cellular glucose uptake without requiring proximal insulin signaling would be desirable for improving glycemic control. The E4orf1 peptide (E4) derived from human adenovirus 36 (Ad36) promotes cellular glucose uptake in vitro and in vivo, independent of insulin. E4 bypasses a part of insulin signaling to upregulate cellular glucose uptake. We tested the hypothesis that E4 requires the distal but not proximal insulin signaling to enhance cellular glucose disposal.Methods3T3-L1 preadipocytes inducibly expressing E4 or a null vector (NV) were treated with inhibitor of insulin receptor (S961), inhibitor of insulin like growth factor-1receptor (IGF-1R) (Picropodophyllin, PPP), PPP+S961, or phosphatidyl inositol-3 kinase (PI3K) inhibitor (Wortmannin, WM). We used PPP and S961 to block the proximal insulin signaling, or WM to block the distal insulin signaling. Cells were exposed to 0 or 100nM insulin.ResultsAs expected, when the proximal or distal insulin signaling was blocked in NV cells, insulin could not enhance pAKT protein abundance, Glut4 translocation, or glucose uptake. Whereas, E4 cells significantly increased pAKT abundance, Glut4 translocation and glucose uptake independent of the presence of insulin or proximal insulin signaling. Enhanced glucose disposal in E4 cells was completely abrogated when the distal insulin signaling was blocked.ConclusionsE4 bypasses the proximal insulin signaling but uses the distal insulin signaling to activate pAkt and in turn Glut4 translocation to improve cellular glucose uptake. E4 offers a promising template to improve glycemic control when the proximal insulin signaling is impaired.

For the past 100 years, oncologists have relentlessly pursued the destruction of tumor cells by surgical, chemotherapeutic or radiation oncological means. Consistent with this focus, treatment plans are typically based on key characteristics of the tumor itself such as disease site, histology and staging based on local, regional and systemic dissemination. Precision medicine is similarly built on the premise that detailed knowledge of molecular alterations of tumor cells themselves enables better and more effective tumor cell destruction. Recently, host factors within the tumor microenvironment including the vasculature and immune systems have been recognized as modifiers of disease progression and are being targeted for therapeutic gain. In this review, we argue that—to optimize the impact of old and new treatment options—we need to take account of an epidemic that occurs independently of—but has major impact on—the development and treatment of malignant diseases. This is the rapidly increasing number of patients with excess weight and its’ attendant metabolic consequences, commonly described as metabolic syndrome. It is well established that patients with altered metabolism manifesting as obesity, metabolic syndrome and chronic inflammation have an increased incidence of cancer. Here, we focus on evidence that these patients also respond differently to cancer therapy including radiation and provide a perspective how exercise, diet or pharmacological agents may be harnessed to improve therapeutic responses in this patient population.

Understanding metabolic and immune regulation inherent to patient populations is key to improving the radiation response for our patients. To date, radiation therapy regimens are prescribed based on tumor type and stage. Patient populations who are noted to have a poor response to radiation such as those of African American descent, those who have obesity or metabolic syndrome, or senior adult oncology patients, should be considered for concurrent therapies with radiation that will improve response. Here, we explore these populations of breast cancer patients, who frequently display radiation resistance and increased mortality rates, and identify the molecular underpinnings that are, in part, responsible for the radiation response and that result in an immune-suppressive tumor microenvironment. The resulting immune phenotype is discussed to understand how antitumor immunity could be improved. Correcting nutrient deficiencies observed in these populations should be considered as a means to improve the therapeutic index of radiation therapy.

Introduction: Health disparities in breast cancer outcomes exist for African American (AA) women who are noted to present with more aggressive cancer with worse survival. Although the underlying reason for this disparity is not apparent, it is likely multifactorial. Interestingly, type 1 insulin-like growth factor receptor (IGF-1R) expression, which plays a critical role in cell growth, survival, and migration, is higher in normal breast tissue in AA women as compared to Caucasian women. Although this has been well established, interventional studies to modulate this pathway have not been performed. We sought to determine if a dietary intervention of caloric restriction could play a role in modulating the IGF-1R pathway to help address the disparities seen in AA breast cancer patients. Methods: On an IRB approved clinical trial, patients were enrolled in a window-of-opportunity clinical trial to assess the effect of caloric restriction, or a 25% reduction of calories from the patients' baseline, on biomarkers in the tumor and blood. Patients recorded their baseline caloric intake for 3-5 days and were then instructed on a target calorie intake for the remainder of the diet. The patients remained on the dietary intervention for 2-12 weeks. Participants had anthropometric evaluation, blood draws to evaluate serum cytokines, tissue collection, and quality of life surveys collected at baseline and completion of diet which was the morning of surgery. Results: We enrolled 19 breast cancer patients between the years 2016 and 2018. The average age of the patients at the time of enrollment was 58 years old with 47% AA and 53% Caucasian. The patients were on the trial for an average of 19 days. Patients lost an average of 4.91 lbs during the trial, with AA patients losing an average of 5.18 lbs and Caucasians losing an average of 4.68 lbs. To determine the importance of IGF-1R in the disparities seen in AA women, we looked at two hundred cytokines from serum samples in patients who underwent caloric restriction. Analysis of the cytokine array data showed that nine cytokines involved in regulating or modulation by the IGF-1R pathway were significantly (p<0.05) downregulated in AA women post-diet. Compared to Caucasian women, AA women showed a significant decrease in IL-12p40 (~51%), VCAM1 (16.8%), IL-2 (28.72%), IL-2Rb (40.81%), CCL28 (36%), ERBB3 (26.6%), PAI-1 (9.4%), Axl (36%) and PDGF-AB (12%). Conclusion: These results demonstrate that caloric restriction significantly downregulated members of the IGF-1R pathway in the AA community. Since this pathway is notably dysregulated in AA patients, an integrated approach, one incorporating dietary changes to alter key pro-survival pathways, should be further investigated to narrow the disparity in breast cancer outcomes in AA patients. Citation Format: Samantha Okere, Anuradha A. Shastri, Kamryn Hines, Pramila Anne, Rita Murphy, Tiziana DeAngelis, Adam Berger, Alliric Willis, Melissa Lazar, Edith Mitchell, Nicole Simone. Caloric restriction may decrease health disparity in AA breast cancer patients due to significant downregulation of the IGF-1R pathway in a window-of-opportunity clinical trial [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-096.