Obesity-altered adipose stem cells promote ER+ breast cancer metastasis through estrogen independent pathways

Rachel A. Sabol, Adam Beighley, Paulina Giacomelli, Rachel M. Wise, Mark A.A. Harrison, Ben A. O’donnnell, Brianne N. Sullivan, Jacob D. Lampenfeld, Margarite D. Matossian, Melyssa R. Bratton, Guangdi Wang, Bridgette M. Collins-Burow, Matthew E. Burow, Bruce A. Bunnell

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish
Article number1419
JournalInternational journal of molecular sciences
Volume20
Issue number6
DOIs
StatePublished - 2 Mar 2019

Keywords

  • Adipose stem cells
  • Breast cancer
  • Estrogen receptor
  • Metastasis
  • Obesity

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