Mammary adipose stromal cells derived from obese women reduce sensitivity to the aromatase inhibitor anastrazole in an organotypic breast model.

Authors:
Molly M Morgan
Molly M Morgan
University of Wisconsin-Madison
Lisa M Arendt
Lisa M Arendt
Tufts University School of Medicine
United States
Elaine T Alarid
Elaine T Alarid
University of Wisconsin-Madison
David J Beebe
David J Beebe
University of Wisconsin-Madison
United States
Brian P Johnson
Brian P Johnson
Essentia Institute of Rural Health
Duluth | United States

FASEB J 2019 Jul 19;33(7):8623-8633. Epub 2019 Apr 19.

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Aromatase inhibitors are the preferred treatment for certain women with estrogen receptor (ER)-positive breast cancer, but evidence suggests that women with obesity experience aromatase inhibitor resistance at higher rates. To compare how stromal cells derived from women who are lean or obese influence response to the aromatase inhibitor (anastrazole), we incorporated patient-derived stroma in a previously characterized MCF7-derived duct model. Coculture with adipose stromal cells enabled the metabolism of testosterone (T) to E, which induced estrogen response element activity, epithelial proliferation, and hyperplasia in MCF7 cells. The effects of T were inhibited by the ER antagonist tamoxifen and aromatase inhibitor anastrazole and were increased by the aromatase inducer dexamethasone. Primary mammary adipose stromal cells derived from women with obesity displayed increased aromatase mRNA compared with lean controls. MCF7-derived ducts cocultured with obese stromal cells exhibited higher maximal aromatization-induced ER transactivation and reduced anastrazole sensitivity, a difference not seen in 2-dimensional coculture. Finally, tamoxifen was more effective than anastrazole at reducing aromatization-induced ER transactivation and proliferation. These findings suggest that patient-specific responses to hormone therapies can be modeled and studied organotypically and add to evidence advocating obesity as a parameter to consider when identifying treatments for patients with ER-positive breast cancer.-Morgan, M. M., Arendt, L. M., Alarid, E. T., Beebe, D. J., Johnson, B. P. Mammary adipose stromal cells derived from obese women reduce sensitivity to the aromatase inhibitor anastrazole in an organotypic breast model.

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Source
http://dx.doi.org/10.1096/fj.201802347RRRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593876PMC

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July 2019

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