Abstract
Obesity, a recognized risk factor for breast cancer in postmenopausal women, is associated with higher mortality rates regardless of menopausal status, which could in part be explained by therapeutic escape. Indeed, adipose microenvironment has been described to influence the efficiency of chemo- and hormonal therapies. Residual cancer stem cells could also have a key role in this process. To understand the mechanisms involved in the reduced efficacy of hormonal therapy on breast cancer cells in the presence of adipose secretome, human adipose stem cells (hMAD cell line) differentiated into mature adipocytes were co-cultured with mammary breast cancer cells and treated with hormonal therapies (tamoxifen, fulvestrant). Proliferation and apoptosis were measured (fluorescence test, impedancemetry, cytometry) and the gene expression profile was evaluated. Cancer stem cells were isolated from mammospheres made from MCF-7. The impact of chemo- and hormonal therapies and leptin was evaluated in this population. hMAD-differentiated mature adipocytes and their secretions were able to increase mammary cancer cell proliferation and to suppress the antiproliferative effect of tamoxifen, confirming previous data and validating our model. Apoptosis and cell cycle did not seem to be involved in this process. The evaluation of gene expression profiles suggested that STAT3 could be a possible target. On the contrary, leptin did not seem to be involved. The study of isolated cancer stem cells revealed that their proliferation was stimulated in the presence of anticancer therapies (tamoxifen, fulvestrant, doxorubicine) and leptin. Our study confirmed the role of adipocytes and their secretome, but above all, the role of communication between adipose and cancer cells in interfering with the efficiency of hormonal therapy. Among the pathophysiological mechanisms involved, leptin does not seem to interfere with the estrogenic pathway but seems to promote the proliferation of cancer stem cells.
Highlights
Breast cancer is the most common cancer among women with 523,000 new cases, which represents13.4% of all cancer cases in Europe and is the leading cause of death in women (138,000, 16.2%) [1].Many epidemiological studies have confirmed the link between obesity and the development of Nutrients 2019, 11, 2839; doi:10.3390/nu11122839 www.mdpi.com/journal/nutrientsNutrients 2019, 11, 2839 cancers such as colon, prostate, and more recently, ovarian cancer
Despite the accumulation of evidence linking obesity to the development of breast cancer, this factor is rarely taken into account and could be decisive in the implementation of individualized treatment for overweight patients
The aim of this study was to investigate (i) how obesity could interfere with hormonal therapies by evaluating the role of the adipose microenvironment in signaling pathways and (ii) the comportment of isolated mammary cancer stem cells (CSCs) in the presence of hormonal therapy and adipokines
Summary
Breast cancer is the most common cancer among women with 523,000 new cases, which represents13.4% of all cancer cases in Europe and is the leading cause of death in women (138,000, 16.2%) [1].Many epidemiological studies have confirmed the link between obesity and the development of Nutrients 2019, 11, 2839; doi:10.3390/nu11122839 www.mdpi.com/journal/nutrientsNutrients 2019, 11, 2839 cancers such as colon, prostate, and more recently, ovarian cancer. Breast cancer is the most common cancer among women with 523,000 new cases, which represents. Despite the accumulation of evidence linking obesity to the development of breast cancer, this factor is rarely taken into account and could be decisive in the implementation of individualized treatment for overweight patients. Adipose tissue is considered to be an endocrine organ capable of secreting soluble factors that can act on surrounding cells and on the composition of the extracellular matrix [4]. These are mainly growth factors, cytokines, adipokines, proteases, or vascular stimulation factors. Breast stroma can undergo phenotypic and functional changes to be active and provide a favorable environment for mammary tumor development [5]
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