Obesity-Altered Adipose Stem Cells Promote ER+ Breast Cancer Metastasis Through Estrogen Independent Pathways.


Department of Chemistry

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Adipose stem cells (ASCs) play an essential role in tumor microenvironments. These cells are altered by obesity (obASCs) and previous studies have shown that obASCs secrete higher levels of leptin. Increased leptin, which upregulates estrogen receptor alpha (ERα) and aromatase, enhances estrogen bioavailability and signaling in estrogen receptor positive (ER+ ) breast cancer (BC) tumor growth and metastasis. In this study, we evaluate the effect of obASCs on ER+ BC outside of the ERα signaling axis using breast cancer models with constitutively active ERα resulting from clinically relevant mutations (Y537S and D538G). We found that while obASCs promote tumor growth and proliferation, it occurs mostly through abrogated estrogen signaling when BC has constitutive ER activity. However, obASCs have a similar promotion of metastasis irrespective of ER status, demonstrating that obASC promotion of metastasis may not be completely estrogen dependent. We found that obASCs upregulate two genes in both ER wild type (WT) and ER mutant (MUT) BC: SERPINE1 and ABCB1. This study demonstrates that obASCs promote metastasis in ER WT and MUT xenografts and an ER MUT patient derived xenograft (PDX) model. However, obASCs promote tumor growth only in ER WT xenografts.


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Funding: Research reported in this publication was supported in part by U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center and OD11104 from the Office of the Director at the National Institutes for Health (BAB). These studies were also supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number TL1TR001418 (RAS). This publication was made possible by funding from the NIMHD-RCMI grant number 5G12MD007595 from the National Institute on Minority Health and Health Disparities and the NIGMS-BUILD grant number 8UL1GM118967 (MRB and GW). This publication was also made possible by the Louisiana Cancer Research Consortium and was facilitated in part by the Cell, Molecular, and Bioinformatics Core facility at Xavier University (MRB and GW). The contents are solely the responsibility of the authors and...