Stromal ER-alpha promotes tumor growth by normalizing an increased angiogenesis
Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel, en activant le récepteur alpha des œstrogènes dans le stroma, l'estradiol favorise la croissance d'un cancer du sein ER-
Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor α (ERα). However, the contribution of stromal expression of ERα in the tumor microenvironment to the pro-tumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17β-estradiol (E2) impacts the microenvironment and modulates tumor development of ERα-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERα-deficient mice, demonstrating a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERα was deficient in Tie2-positive cells, but still expressed by bone marrow derived cells. These results were extended by clinical evidence of ERα-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore suggest that E2 promotes the growth of ERα-negative cancer cells through the activation of stromal ERα (not hematopoiteic but Tie2-dependent expression of ERα), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumor demand preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment