BACKGROUND: Estrogen is the leading etiologic factor for endometrial cancer. Estrogen-induced proliferation of endometrial epithelial cells normally requires paracrine growth factors produced by stromal cells. Epidemiologic evidence indicates that dietary soy prevents endometrial cancer, and implicates the phytoestrogen genistein in this effect. However, results from previous studies are conflicting regarding the effects of genistein on hormone responsive cancers. METHODS: The effects of estrogen and genistein on proliferation of Ishikawa (IK) endometrial adenocarcinoma cells were examined in co-cultures of IK cells with endometrial stromal cells, recapitulating the heterotypic cell-to-cell interactions observed in vivo. The roles of estrogen receptor (ER)α and ERβ were evaluated using ERα and ERβ specific agonists. ER activation and cell proliferation in the IK epithelial cells were determined by alkaline phosphatase assay and Coulter counter enumeration, respectively. RESULTS: Both estrogen and genistein increased estrogen receptor-induced gene activity in IK cells over a range of concentrations. Estrogen alone but not genistein increased IK proliferation in co-cultures. When primed by estrogen treatment, increasing concentrations of genistein produced a biphasic effect on IK proliferation: nM concentrations inhibited estrogen-induced proliferation while μM concentrations increased proliferation. Studies with an ERβ-specific agonist produced similar results. Genistein did not influence the effects of estrogen on IK proliferation in monoculture. CONCLUSIONS: Our study indicates that nutritionally relevant concentrations (nM) of genistein inhibit the proliferative effects of estrogen on endometrial adenocarcinoma cells presumably through activation of stromal cell ERβ. We believe that sub-micromolar concentrations of genistein may represent a novel adjuvant for endometrial cancer treatment and prevention.
BACKGROUND: Estrogen is the leading etiologic factor for endometrial cancer. Estrogen-induced proliferation of endometrial epithelial cells normally requires paracrine growth factors produced by stromal cells. Epidemiologic evidence indicates that dietary soy prevents endometrial cancer, and implicates the phytoestrogen genistein in this effect. However, results from previous studies are conflicting regarding the effects of genistein on hormone responsive cancers. METHODS: The effects of estrogen and genistein on proliferation of Ishikawa (IK) endometrial adenocarcinoma cells were examined in co-cultures of IK cells with endometrial stromal cells, recapitulating the heterotypic cell-to-cell interactions observed in vivo. The roles of estrogen receptor (ER)α and ERβ were evaluated using ERα and ERβ specific agonists. ER activation and cell proliferation in the IK epithelial cells were determined by alkaline phosphatase assay and Coulter counter enumeration, respectively. RESULTS: Both estrogen and genistein increased estrogen receptor-induced gene activity in IK cells over a range of concentrations. Estrogen alone but not genistein increased IK proliferation in co-cultures. When primed by estrogen treatment, increasing concentrations of genistein produced a biphasic effect on IK proliferation: nM concentrations inhibited estrogen-induced proliferation while μM concentrations increased proliferation. Studies with an ERβ-specific agonist produced similar results. Genistein did not influence the effects of estrogen on IK proliferation in monoculture. CONCLUSIONS: Our study indicates that nutritionally relevant concentrations (nM) of genistein inhibit the proliferative effects of estrogen on endometrial adenocarcinoma cells presumably through activation of stromal cell ERβ. We believe that sub-micromolar concentrations of genistein may represent a novel adjuvant for endometrial cancer treatment and prevention.
Authors: P S Cooke; D L Buchanan; P Young; T Setiawan; J Brody; K S Korach; J Taylor; D B Lubahn; G R Cunha Journal: Proc Natl Acad Sci U S A Date: 1997-06-10 Impact factor: 11.205
Authors: Guillermo Rimoldi; Julie Christoffel; Dana Seidlova-Wuttke; Hubertus Jarry; Wolfgang Wuttke Journal: Environ Health Perspect Date: 2007-12 Impact factor: 9.031
Authors: Kim M Malloy; Jiandong Wang; Leslie H Clark; Ziwei Fang; Wenchuan Sun; Yajie Yin; Weimin Kong; Chunxiao Zhou; Victoria L Bae-Jump Journal: Am J Transl Res Date: 2018-03-15 Impact factor: 4.060
Authors: Javad Sharifi-Rad; Cristina Quispe; Muhammad Imran; Abdur Rauf; Muhammad Nadeem; Tanweer Aslam Gondal; Bashir Ahmad; Muhammad Atif; Mohammad S Mubarak; Oksana Sytar; Oxana Mihailovna Zhilina; Ekaterina Robertovna Garsiya; Antonella Smeriglio; Domenico Trombetta; Daniel Gabriel Pons; Miquel Martorell; Susana M Cardoso; Ahmad Faizal Abdull Razis; Usman Sunusi; Ramla Muhammad Kamal; Lia Sanda Rotariu; Monica Butnariu; Anca Oana Docea; Daniela Calina Journal: Oxid Med Cell Longev Date: 2021-07-19 Impact factor: 6.543