Introduction: Obesity is associated with a worse prognosis in breast cancer, including the less aggressive ER+ luminal A subtype, but the mechanisms by which it promotes disease progression are unclear, making treatment difficult. Obese breast cancer patients have a higher risk of a more aggressive disease compared to lean patients, which is associated with treatment resistance and metastasis. The mechanisms promoting obesity-driven metastasis are not understood, but several studies have indicated that obesity is associated with a “stem-like” phenotype. A “reprogramming” occurs, transforming stationary, epithelial cells to motile, malignant cells that exhibit a more aggressive phenotype than their stromal counterparts. Our data suggest that in vitro exposure of luminal A breast cancer cells to obese conditions may induce an epithelial to mesenchymal transition (EMT), which is characterized by a more stem-like phenotype, resistance to treatment (chemo, hormone and radiation), as well as greater metastatic potential. This has let us to hypothesize that one critical mechanism by which obesity promotes a more aggressive disease is through inducing an EMT reprogramming, resulting in a more stem-like phenotype. Methods and Results: Both in vitro and translational approaches will be done to determine if obesity induces epigenetic reprograming associated with a more stem-like phenotype. MCF-7 ER+ breast cancer cells exposed to 2% sera from obese (BMI ≥ 30) postmenopausal women demonstrated a significant increase in expression of both SNAIL1 and TWIST transcription factors (9-fold and 4-fold, respectively) which are implicated in EMT and potentially stem-cell programming, compared to those exposed to sera from lean women. Current studies are underway to determine if this is observed in other ER+ luminal A cell lines, including T47D, and whether induced changes in these transcription factors results in changes in signaling pathways associated with EMT, including TGFβ, which can activate the PI3K–AKT, ERK MAPK, p38 MAPK and JNK pathways and WNT signaling, which promotes EMT by stabilizing β-catenin. Additionally, the luminal A cell lines will be assessed for changes in other factors known to modulate breast cancer cell programming, including KLF4, OCT4, SOX2, and NANOG. Conclusions: Our earlier studies have demonstrated that obesity promotes a more aggressive disease even in luminal A disease. The mechanisms for this remain unclear. Our exciting preliminary findings suggest that obesity might induce a reprogramming of the luminal A well-differentiated cell to a more stem-like phenotype. Our results will lay an important foundation for understanding how obesity modulates breast cancer disease progression, whether this programming may provide therapeutic target to improve response and overall survival in the obese patient. Citation Format: Hayden A, Quach D, Galvan G, Patodia R, Brenner A, deGraffenried L. Obesity-induced EMT in luminal A breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-04-03.
Purpose: The objective of this study is to determine the impact of exposure to obesity-related systemic factors on fatty acid synthase enzyme (FASN) expression in breast cancer cells. Methods: MCF-7 breast cancer cells were exposed to sera from patients having obesity or not having obesity and subjected to quantitative reverse transcription polymerase chain reaction (RT-qPCR). Subsequent MTT and colony-forming assays using both MCF-7 and T-47D cells exposed to sera and treated with or without FASN inhibitor, TVB-3166, were used. MCF-7 cells were then treated with insulin and the sterol regulatory element–binding protein (SREBP) processing inhibitor, betulin, prior to analysis of FASN expression by quantitative RT-qPCR and western blot. Insulin-induced SREBP-FASN promoter binding was analyzed by chromatin immunoprecipitation with an anti-SREBP antibody. Results: In response to sera exposure (body mass index [BMI] >30) there was an increase in FASN expression in breast cancer cells. Furthermore, treatment with the FASN inhibitor, TVB-3166, resulted in a decreased breast cancer cell survival and proliferation while increasing apoptosis upon sera exposure (BMI >30). Insulin-exposed MCF-7 cells exhibited an increased FASN messenger RNA and protein expression, which is abrogated upon SREBP inhibition. In addition, insulin exposure induced enhanced SREBP binding to the FASN promoter. Conclusions: Our results implicate FASN as a potential mediator of obesity-induced breast cancer aggression and a therapeutic target of patients with obesity-induced breast cancer.
Background: Obesity is associated with prostate cancer progression and mortality. Previous studies in our laboratory suggest that obesity drives prostate cancer progression in part by increasing macrophage recruitment and by polarizing macrophages in the tumor microenvironment into a tumor promoting M2/TAM phenotype. Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has been used for several decades in transplant patients, and in the last several years has been shown to be an effective disease suppressor in certain cancer types. Intriguingly, mTOR has been shown to be especially important for M2 polarization and stabilization. Hypothesis: Based upon published data and our preliminary studies, we hypothesize that rapamycin will selectively target obesity-polarized macrophages and will provide a survival benefit to the obese prostate cancer patient. Methods: To address this hypothesis, we used our in vitro model of obesity-induced macrophage polarization that includes two different prostate cancer cell lines, macrophages, and sera from obese and non-obese men. qPCR was used to measure expression levels of markers associated with an M2/TAM phenotype. MTT assays were conducted to measure cell viability, and flow cytometry and Western blot analyses were used to determine cell cycle status and apoptosis. Results: Obese conditions increased expression of M2/TAM markers in macrophages and rapamycin selectively decreased viability of obesity-activated M2/TAMs compared to M1 macrophages. Conclusions: Our in vitro study suggests that obesity promotes a tumor-associated phenotype in macrophages and that the mTOR pathway is involved in the survival of M2/TAM macrophages. This study offers a novel mechanistic approach to treat obese patients with prostate cancer. Citation Format: Gloria C. Galván, Tommy Pham, Brittany Harlow, Christian Johnson, Riddhi Patodia, Duan Quach, Michael A. Liss, Linda A. deGraffenried. Rapamycin selectively targets obesity-polarized macrophages in the prostate tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4004. doi:10.1158/1538-7445.AM2017-4004
e14619 Background: Obesity is associated with poor breast cancer outcomes. Our prior data suggested a positive feedback loop whereby circulating factors associated with obesity induce the COX-2 enzyme, resulting in increased pro-inflammatory cytokine prostaglandin E2 (PGE2), which can then increase aromatase levels. In order to establish a better understanding of baseline PGE2 levels, as well as select the proper COX2 inhibitor for prospective study, we performed a randomized study of aspirin (ASA), fish oil (DHA/EPA), and the combination in postmenopausal women of varying body habitus and assessed changes in cytokines. Methods: Women were recruited and randomly assigned into 3 interventions: ASA 81mg, docosahexaenoic acid (DHA, 1500mg) with eicosapentaenoic acid (EPA, 2500mg), or combination ASA and DHA/EPA (DUAL). Blood was collected before and after 28 days of supplementation, and 27 cytokines were assessed by Luminex array (Millipore); PGE2 was measured by ELISA. Investigators were blinded until analysis was complete. Statistical analyses were performed in R. Results: 110 patients were included: 90% participants white; of which 50% Hispanic; average BMI 31.5±0.67; and age: 60.1±0.58. Cytokines were not correlated with demographic variables. At baseline inflammatory cytokines IL-6 and Eotaxin were correlated with BMI ((p > 0.029 and p > 0.017, respectively). After 28 days of DHA/EPA BMI was correlated with Eotaxin, Il-2, IL-7 and GM-CSF (p < 0.05), in ASA group correlation was significant only with IL-2 (cor.coef= 0.58). Two sample t-test showed significant difference between DUAL and ASA or DHA/EPA for IL-6 (p = 0.008 and p = 0.034, respectively), and for IL-2 only between DUAL and ASA (p = 0.039). Furthermore, impact on PGE2 was observed with ASA with 81% obtaining a decrease from baseline (median change -28%); by comparison 55.1% (-1%) and 65.6% (-22%) of subjects showed decrease in the DUAL and DHA/EPA groups respectively. Level of macrophage inflammatory proteins (MIP-1b) were lower in the DUAL group compare to ASA (p < 0.014). Conclusions: Chronic inflammatory cytokines are correlated with obesity, and may be modified by use of ASA and DHE/EPA. This strategy may be useful in the secondary prevention setting. Clinical trial information: NCT02062255.
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