OR29-04 Tamoxifen Effects on Adipocyte Progenitors Link Breast Cancer Therapy to Diabetes Risk

Abstract Disclosure: N.S. Thomas: None. Nisha S Thomas1, Rebecca L. Scalzo2, Elizabeth A Wellberg1 1 University of Oklahoma Health Science Center, Oklahoma City, OK,731042 University of Colorado Anschutz Medical Campus; Aurora, CO, 80045 Women diagnosed with estrogen receptor-positive (ER+) breast cancer who receive endocrine therapy have 30% increased risk of developing type 2 diabetes (T2D) when compared to those receiving other breast cancer treatments. Of all the T2D cases diagnosed after breast cancer treatment, 48% are attributable to the prescribed therapy, largely due to tamoxifen treatment. Estrogen and endocrine therapies interact with nuclear and extranuclear estrogen receptors (ERα/β and GPER1) in metabolic tissues; therefore, any treatment that blocks ER will impact whole-body metabolism. Importantly, tamoxifen is a GPER1 agonist. We recently found that tamoxifen and estrogen deprivation therapy impaired glucose tolerance, promoted weight gain, and increased hepatic steatosis in high-fat- but not low-fat-fed female mice. In adipose tissue of high-fat-fed female mice, endocrine therapies depleted the adipocyte progenitors and promoted mature adipocyte hypertrophy, providing a plausible mechanism through which endocrine therapies can promote T2D in breast cancer survivors. Single-cell RNA sequencing of CD29+ subcutaneous adipose stromal cells revealed that, in high fat-fed female mice, endocrine therapy inhibited the expression of Wnt1-inducible signaling pathway protein 2 (Wisp2), which helps to maintain the precursor populations. In subcutaneous adipocyte precursor cells, Esr1 and Wisp2 were highly expressed in progenitors compared to the committed preadipocytes. Estrogen treatment induced Wisp2 expression in an ERα dependent manner. Estrogen and/or Wisp2 treatment increased the progenitor cell population, while tamoxifen decreased the proliferation of these cells. Wisp2 knockdown in adipocyte precursor cells upregulated markers of inflammation and senescence, similar to tamoxifen treatment. The effects of tamoxifen on genes associated with inflammation and senescence could be prevented by co-treatment with exogenous Wisp2 protein. In vitro, treatment with the GPER1 agonist, G1, mimicked the effects of tamoxifen by suppressing progenitor cell markers and increasing genes associated with senescence, suggesting that tamoxifen impacts adipose tissue in part through GPER1 activation. In vivo, blocking GPER1 with the antagonist CIMBA during tamoxifen treatment prevented body fat gain and reduced fasting insulin levels in high-fat-fed female mice. This study reveals the complex role and potential mechanisms of ER signaling that support hyperplastic adipose tissue expansion, a contributing factor to the excess risk for T2D in breast cancer survivors after endocrine therapy. Presentation: Monday, July 14, 2025