title: Stromal estrogen receptor-α promotes tumor growth by normalizing an increased angiogenesis.
abstract: 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 protumoral 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, showing a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERα was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ERα-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ERα-negative cancer cells through the activation of stromal ERα (extra-hematopoietic Tie-2 positive cells), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumors, thereby preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment.
authors.affiliation: INSERM U1048, I2MC, IFR31, UPS, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Péqueux
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raymond-Letron
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Frédéric
authors.initials: F
authors.lastname: Boudou
authors.forename: Marine
authors.initials: M
authors.lastname: Adlanmerini
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Fouque
authors.forename: Philippe
authors.initials: P
authors.lastname: Rochaix
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Andrée
authors.initials: A
authors.lastname: Krust
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Laurent
authors.initials: L
authors.lastname: Brouchet
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arnal
authors.forename: Françoise
authors.initials: F
authors.lastname: Lenfant
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008545:Melanoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000473:pathology*; D017154:Stromal Cells; D059016:Tumor Microenvironment
chemical_list: D047628:Estrogen Receptor alpha; D004958:Estradiol