Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

FXR Agonism with Bile Acid Mimetic Reduces Pre-clinical Triple-Negative Breast Cancer Burden

Sydney Clarice Joseph
ORCID logo ,
Samson Eugin Simon
ORCID logo ,
Margaret Sue Bohm
,
Minjeong Kim
,
Madeline E Pye
,
Boston William Simmons
,
Dillon Garen Graves
,
Stacey Marchelle Thomas-Gooch
,
Ubaid A Tanveer
,
Jeremiah Ray Holt
,
Suriyan Ponnusamy
,
Laura M Sipe
ORCID logo ,
D. Neil Hayes
,
Katherine Loree Cook
ORCID logo ,
Ramesh Narayanan
,
Joseph F Pierre
* ,
Liza Makowski
* ORCID logo
Version 1 : Received: 25 January 2024 / Approved: 25 January 2024 / Online: 26 January 2024 (11:49:34 CET)

A peer-reviewed article of this Preprint also exists.

Joseph, S.C.; Eugin Simon, S.; Bohm, M.S.; Kim, M.; Pye, M.E.; Simmons, B.W.; Graves, D.G.; Thomas-Gooch, S.M.; Tanveer, U.A.; Holt, J.R.; Ponnusamy, S.; Sipe, L.M.; Hayes, D.N.; Cook, K.L.; Narayanan, R.; Pierre, J.F.; Makowski, L. FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden. Cancers 2024, 16, 1368. Joseph, S.C.; Eugin Simon, S.; Bohm, M.S.; Kim, M.; Pye, M.E.; Simmons, B.W.; Graves, D.G.; Thomas-Gooch, S.M.; Tanveer, U.A.; Holt, J.R.; Ponnusamy, S.; Sipe, L.M.; Hayes, D.N.; Cook, K.L.; Narayanan, R.; Pierre, J.F.; Makowski, L. FXR Agonism with Bile Acid Mimetic Reduces Pre-Clinical Triple-Negative Breast Cancer Burden. Cancers 2024, 16, 1368.

Abstract

Obesity is one of the most prevalent chronic diseases and has become a global epidemic. Obesity leads to a greater risk of breast cancer (BC), metastases, recurrence, and decreased survival. For sustained weight loss, bariatric surgery is effective as a long-term solution. Bariatric surgery is associated with improved outcomes of several cancers including BC, although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Indeed, patients with greater expression of the bile acid receptor FXR displayed improved survival in specific BC subtypes. Patients with tumors that are estrogen receptor negative (ER-) displayed significantly elevated survival with higher FXR (NR1H4) expression compared to lower expression. FXR is a nuclear hormone receptor activated by bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would display anticancer effects. Indeed, FXR agonism by the bile acid mimetic known commercially as OCALIVA (“OCA”), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor (GPBAR1, TGR5) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. Findings suggest that FXR is a tumor suppressor gene with high potential for personalized therapeutic strategies for individuals with BC.

Keywords

nuclear hormone receptor, agonist, bile acid receptor, FXR, TGR5, triple-negative breast cancer, TNBC

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download PDF Download Supplementary

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0
Get PDF Supplementary Files Cite Share 0
Bookmark BibSonomy Mendeley Reddit Delicious
×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.