Tamoxifen targets Wisp2 to impair subcutaneous adipocyte progenitor self-renewal and adipogenic differentiation

Breast cancer endocrine therapy, including tamoxifen, systemically disrupts estrogen receptor signaling and increases type 2 diabetes (T2D) risk in women. Hyperplastic adipose tissue expansion, especially in subcutaneous depots, facilitates nutrient storage and attenuates inflammation during a chronic positive energy balance and is impaired in the absence of estrogen. Adipocyte progenitors are renewed through Wnt signaling pathway activation, however the the mechanisms that explain the depletion of these cells during endocrine therapy are not defined. Here we show the direct impact of tamoxifen on proliferation, renewal, and differentiation in subcutaneous adipose stromal cells from humans and adult mice. In obesity, the Wnt1 inducible signaling pathway protein 2 (Wisp2) was lost in adipocyte progenitors following endocrine therapy. Wisp2 gain and loss of function studies defined the link between estrogen signaling and adipocyte progenitor maintenance. We found that tamoxifen treatment disrupts the protection of adipocyte progenitors by estrogen, mediated through suppression of Wisp2. These studies reveal effects of tamoxifen therapy that precede and could influence T2D development in breast cancer survivors.