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

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Abstract

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.

Authors

Meghan J. Price, Annee D. Nguyen, Corinne H. Strawser, Trupti Trivedi, Cesar C.D. Baeta, Catherine Lavau, Jovita K. Byemerwa, Debarati Mukherjee, Suzanne E. Wardell, Sandeep Artham, Vardhman Kumar, Shyni Varghese, C. Rory. Goodwin