Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP)

Abstract

IntroductionClinical 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.MethodsWe 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.ResultsAdipocytes 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.ConclusionsCollectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1088-6) contains supplementary material, which is available to authorized users.

Integration of genetic, transcriptomic, and clinical data provides insight into 16p11.2 and 22q11.2 CNV genes

“…Third, these genes could have a true BMIincreasing effect. Consistent with our in silico finding, MVP is upregulated in adipocytes and cells co-cultured with adipocytes from obese individuals [86,87]. If KCTD13 and MVP have a true BMI-increasing effect, the 16p11.2 region contains both BMI-increasing and BMIdecreasing genes, and the effect of the BMI-decreasing genes is stronger.…”

Decreased Efficacy of Doxorubicin Corresponds With Modifications in Lipid Metabolism Markers and Fatty Acid Profiles in Breast Tumors From Obese vs. Lean Mice

“…In addition, poor treatment outcomes are also reported in overweight and obese breast cancer patients evident by larger tumor sizes and poor clinical outcomes (7,18,42,43) especially those treated with doxorubicin (42,44). It was also reported that DIO decreased the efficacy of breast cancer treatment protocols in pre-clinical animal models (33,45).…”

“…Furthermore, a dysregulation of cytokines (i.e., increased IL-6, TNF-α, and IL-1β) and adipokines, such as increased leptin and decreased adiponectin (80)(81)(82)(83) has been shown to induces transcriptional changes. For example leptin has been shown to inhibit lipogenesis by altering the expression of transcription factors involved in lipid metabolism (7,45). The outcome is altered adipocyte endocrine functionality which can favor tumor cells to produce more adipokines (83).…”

Factors Associated with the Prevalence of Breast Cancer Risk: Perception of Northern Saudi Civic

“…Several studies reported that overweight and obesity elevate the risk of breast cancer, particularly in pre-and post-menopausal females [14] [15]. Clinical studies propose that obesity, besides promoting breast cancer aggressiveness, is associated with a decline in chemotherapy effectiveness, though the process intricate still indefinable [16].…”