title: Differential roles of ERα and ERβ in normal and neoplastic development in the mouse mammary gland.
abstract: The present experiments were performed to determine the roles of estrogen receptors α and β (ERα and ERβ) in normal and neoplastic development in the mouse mammary gland. In wild-type mice, in vivo administration of estradiol (E) + progesterone (P) stimulated mammary ductal growth and alveolar differentiation. Mammary glands from mice in which the ERβ gene has been deleted (βERKO mice) demonstrated normal ductal growth and differentiation in response to E + P. By contrast, mammary glands from mice in which the ERα gene has been deleted (αERKO mice) demonstrated only rudimentary ductal structures that did not differentiate in response to E + P. EGF demonstrates estrogen-like activity in the mammary glands of αERKO mice: treatment of αERKO mice with EGF + P (without E) supported normal mammary gland development, induced expression of progesterone receptor (PR), and increased levels of G-protein-coupled receptor (GPR30) protein. Mammary gland development in βERKO mice treated with EGF + P was comparable to that of wild-type mice receiving EGF + P; EGF had no statistically significant effects on the induction of PR or expression of GPR30 in mammary glands harvested from either wild-type mice or βERKO mice. In vitro exposure of mammary glands to 7,12-dimethylbenz[a]anthracene (DMBA) induced preneoplastic mammary alveolar lesions (MAL) in glands from wild-type mice and βERKO mice, but failed to induce MAL in mammary glands from αERKO mice. Microarray analysis of DMBA-treated mammary glands identified 28 functional pathways whose expression was significantly different in αERKO mice versus both βERKO and wild-type mice; key functions that were differentially expressed in αERKO mice included cell division, cell proliferation, and apoptosis. The data demonstrate distinct roles for ERα and ERβ in normal and neoplastic development in the mouse mammary gland, and suggest that EGF can mimic the ERα-mediated effects of E in this organ.
authors.affiliation: IIT Research Institute, Chicago, Illinois, United States of America.
authors.forename: Rajendra G
authors.initials: RG
authors.lastname: Mehta
authors.affiliation: IIT Research Institute, Chicago, Illinois, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Hawthorne
authors.affiliation: IIT Research Institute, Chicago, Illinois, United States of America.
authors.forename: Rajeshwari R
authors.initials: RR
authors.lastname: Mehta
authors.affiliation: GenUs Biosystems, Northbrook, Illinois, United States of America.
authors.forename: Karen E O
authors.initials: KE
authors.lastname: Torres
authors.affiliation: IIT Research Institute, Chicago, Illinois, United States of America.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Peng
authors.affiliation: IIT Research Institute, Chicago, Illinois, United States of America.
authors.forename: David L
authors.initials: DL
authors.lastname: McCormick
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, United States of America.
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004958:Estradiol / Q000008:administration & dosage; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D011374:Progesterone / Q000008:administration & dosage; D060888:Real-Time Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D017931:DNA Primers; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C532507:GPER1 protein, mouse; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D011374:Progesterone; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene