UDP-6-glucose dehydrogenase in hormonally responsive breast cancers

Survival for metastatic breast cancer is low and thus, continued efforts to treat and prevent metastatic progression are critical. Estrogen is shown to promote aggressive phenotypes in multiple cancer models irrespective of estrogen receptor (ER) status. Similarly, UDP-Glucose 6-dehydrogenase (UGDH) a ubiquitously expressed enzyme involved in extracellular matrix precursors, as well as hormone processing increases migratory and invasive properties in cancer models. While the role of UGDH in cellular migration is defined, how it intersects with and impacts hormone signaling pathways associated with tumor progression in metastatic breast cancer has not been explored. Here we demonstrate that UGDH knockdown blunts estrogen-induced tumorigenic phenotypes (migration and colony formation) in ER+ and ER- breast cancer in vitro . Knockdown of UGDH also inhibits extravasation of ER- breast cancer ex vivo , primary tumor growth and animal survival in vivo in both ER+ and ER- breast cancer. We also use single cell RNA-sequencing to demonstrate that our findings translate to a human breast cancer clinical specimen. Our findings support the role of estrogen and UGDH in breast cancer progression provide a foundation for future studies to evaluate the role of UGDH in therapeutic resistance to improve outcomes and survival for breast cancer patients. ### Competing Interest Statement Disclosures: The authors have no disclosures relevant to the current work, nor any true/perceived conflicts of interest. Disclosures outside of the current work: C. Rory Goodwin: Received grants from the Robert Wood Johnson Harold Amos Medical Faculty Development Program, the Federal Food and Drug Administration, Duke Bass Connections, and the NIH 1R01DE031053-01A1. Consultant for Stryker and Medtronic. Deputy Editor for Spine. Patent Application/invention disclosures outside of the current work.