RESUMEN
In addition to the major subcutaneous and visceral adipose tissues (AT), other adipose depots are dispersed throughout the body and are found in close interaction with proximal organs such as mammary and periprostatic AT (MAT and PPAT respectively). These ATs have an effect on proximal organ function during physiological processes and diseases such as cancer. We highlighted here some of their most distinctive features in terms of tissular organization and responses to external stimuli and discussed how obesity affects them based on our current knowledge.
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Tejido Adiposo , Obesidad , Humanos , Tejido Adiposo/fisiología , Femenino , Obesidad/fisiopatología , Neoplasias/patología , Animales , Mama/fisiología , Mama/patología , Neoplasias de la Mama/patología , Glándulas Mamarias Humanas/fisiología , Glándulas Mamarias Humanas/patología , Grasa Intraabdominal , Grasa Subcutánea/fisiología , Grasa Subcutánea/patologíaRESUMEN
Nuclear receptor coactivator 3 (NCoA3) is a transcriptional coactivator of NFκB and other factors, which is expressed at relatively low levels in normal cells and is amplified or overexpressed in several types of cancer, including breast tumors. NCoA3 levels have been shown to be decreased during adipogenesis; however, its role in tumorsurrounding adipose tissue (AT) remains unknown. Therefore, the present study assessed the modulation of NCoA3 in breast cancerassociated adipocytes and evaluated its association with the expression of inflammatory markers. 3T3L1 adipocytes were stimulated with conditioned medium from human breast cancer cell lines and the expression levels of NCoA3 were evaluated by reverse transcriptionquantitative (q)PCR. NFκB activation was measured by immunofluorescence, and tumor necrosis factor and monocyte chemoattractant protein 1 levels were analyzed by qPCR and dot blot assays. The results obtained from the in vitro model were supported using mammary AT (MAT) from female mice, MAT adjacent to tumors from patients with breast cancer and bioinformatics analysis. The results revealed that adipocytes expressing high levels of NCoA3 were mainly associated with a proinflammatory profile. In 3T3L1 adipocytes, NCoA3 downregulation or NFκB inhibition reversed the expression of inflammatory molecules. In addition, MAT from patients with a worse prognosis exhibited high levels of this coactivator. Notably, adipocyte NCoA3 levels could be modulated by inflammatory signals from tumors. The modulation of NCoA3 levels in synergy with NFκB activity in MAT in a tumor context could be factors required to establish breast cancerassociated inflammation. As adipocytes are involved in the development and progression of breast cancer, this signaling network deserves to be further investigated to improve future tumor treatments.
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Neoplasias de la Mama , Coactivador 3 de Receptor Nuclear , Animales , Femenino , Humanos , Ratones , Adipocitos/metabolismo , Neoplasias de la Mama/patología , FN-kappa B/genética , FN-kappa B/metabolismo , Coactivador 3 de Receptor Nuclear/genética , Coactivador 3 de Receptor Nuclear/metabolismo , Regulación hacia Arriba , Células 3T3-L1RESUMEN
Adiposity and diabetes affect breast cancer (BC) progression. We addressed whether glucose may affect the interaction between mammary adipose tissue-derived mesenchymal stromal/stem cells (MAT-MSCs) and BC cells. Two-dimensional co-cultures and spheroids were established in 25 mM or 5.5 mM glucose (High Glucose-HG or Low Glucose-LG) by using MAT-MSCs and MCF7 or MDA-MB231 BC cells. Gene expression was measured by qPCR, while protein levels were measured by cytofluorimetry and ELISA. CD44high/CD24low BC stem-like sub-population was quantified by cytofluorimetry. An in vivo zebrafish model was assessed by injecting spheroid-derived labeled cells. MAT-MSCs co-cultured with BC cells showed an inflammatory/senescent phenotype with increased abundance of IL-6, IL-8, VEGF and p16INK4a, accompanied by altered levels of CDKN2A and LMNB1. BC cells reduced multipotency and increased fibrotic features modulating OCT4, SOX2, NANOG, αSMA and FAP in MAT-MSCs. Of note, these co-culture-mediated changes in MAT-MSCs were partially reverted in LG. Only in HG, MAT-MSCs increased CD44high/CD24low MCF7 sub-population and promoted their ability to form mammospheres. Injection in zebrafish embryos of HG spheroid-derived MCF7 and MAT-MSCs was followed by a significant cellular migration and caudal dissemination. Thus, MAT-MSCs enhance the aggressiveness of BC cells in a HG environment.
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Mammary adipose tissue (AT) is necessary for breast epithelium. However, in breast cancer (BC), cell-cell interactions are deregulated as the tumor chronically modifies AT microenvironment. In turn, breast AT evolves to accommodate the tumor, and to participate to its dissemination. Among AT cells, adipocytes and their precursor mesenchymal stem cells (MSCs) play a major role in supporting tumor growth and dissemination. They provide energy supplies and release a plethora of factors involved in cancer aggressiveness. Here, we discuss the main molecular mechanisms underlining the interplay between adipose (adipocytes and MSCs) and BC cells. Following close interactions with BC cells, adipocytes lose lipids and change morphology and secretory patterns. MSCs also play a major role in cancer progression. While bone marrow MSCs are recruited by BC cells and participate in metastatic process, mammary AT-MSCs exert a local action by increasing the release of cytokines, growth factors and extracellular matrix components and become principal actors in cancer progression. Common systemic metabolic diseases, including obesity and diabetes, further modify the interplay between AT and BC. Indeed, metabolic perturbations are accompanied by well-known alterations of AT functions, which might contribute to worsen cancer phenotype. Here, we highlight how metabolic alterations locally affect mammary AT and interfere with the molecular mechanisms of bidirectional communication between adipose and cancer cells.
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PURPOSE: To assess the association of fatty acid levels in mammary adipose tissue of postmenopausal women with the presence of breast cancer using the Gradient-echo Spectroscopic Imaging (GSI). MATERIALS AND METHODS: Unilateral GSI was performed at 3 T in 61 postmenopausal women undergoing breast MRI exams. The study included 19 women with breast cancer, 23 women with benign/high risk lesions, and 19 women with a history of cancer. Voxel-wise spectral analysis of fatty acids was conducted to measure relative portions of monounsaturated (MUFA), polyunsaturated (PUFA), and saturated fatty acids (SFA) in each voxel. The voxels within mammary adipose tissue were automatically selected and their median fatty acid fractions were used for quantitative analysis. Statistical analyses were performed using χ2 test, one-way analysis of variance (ANOVA) with Tukey-Kramer multiple comparison tests, and linear regression. RESULTS: Postmenopausal women with malignancies had significantly higher SFA (0.336 ± 0.038) in mammary adipose tissue compared to those with benign disease (0.283 ± 0.046, p = 0.0008) and to those with a history of breast cancer (0.287 ± 0.050, p = 0.0038). Postmenopausal women with malignant lesions had significantly lower MUFA (0.352 ± 0.041) compared to those with benign disease (0.401 ± 0.043, p = 0.0032) and with history of breast cancer (0.388 ± 0.055, p = 0.0484). The history of cancer group had a significant correlation (r = 0.60, p = 0.006) between SFA and BMI, and the cancer group had a significant correlation (r = 0.57, p = 0.010) between PUFA and BMI. CONCLUSIONS: Fatty acid composition of mammary adipose tissue, particularly higher SFA and lower MUFA, may be associated with breast cancer. The GSI method utilizes an automated voxel-based analysis to measure fatty acid composition, and may be used to assess the role of mammary adipose tissue in cancer development and progress.
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Tejido Adiposo/química , Neoplasias de la Mama/metabolismo , Mama/química , Ácidos Grasos/metabolismo , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Persona de Mediana Edad , Posmenopausia/fisiología , Estudios RetrospectivosRESUMEN
INTRODUCTION: Clinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated. METHODS: We used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer. RESULTS: Adipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases. CONCLUSIONS: Collectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.