Estrogen promotes tumor phenotypes in ER+ and ER– breast cancer through UGDH-GPR30

Estrogen can promote aggressive tumor phenotypes in estrogen receptor–positive (ER + ) breast cancer; however, ER – cell lines are not widely considered estrogen responsive. Noncanonical estrogen-stimulated pathways such as the membrane-bound G protein–coupled estrogen receptor ( GPR30 ) can mediate migratory and proliferative phenotypes in breast cancer and are postulated to promote resistance to aromatase therapies. Moreover, dysregulation of UDP-glucose 6-dehydrogenase ( UGDH ), a ubiquitously expressed enzyme critical to the metabolism of UDP-glucuronic acid into extracellular matrix precursors and hormone regulation, is associated with tumorigenesis. Here, we illustrated the impact of estrogen stimulation on tumor phenotypes in ER + and ER – cell models in vitro and in vivo. We then demonstrated UGDH ’s association with metastatic breast cancer via single-cell sequencing of patient specimens. Genetic knockdown of UGDH blunted estrogen-stimulated tumor phenotypes in vitro, ex vivo, and in vivo using both ER + and ER – breast cancer lines. Finally, we demonstrated that UGDH knockdown blunted noncanonical estrogen stimulation through GPR30 . Ultimately, our study validated prior studies demonstrating estrogen-responsive malignant phenotypes in ER – breast cancer and demonstrated that estrogen-stimulated breast cancer progression can be mediated through noncanonical pathways (e.g., UGDH/GPR30 ), regardless of ER status.