title: Mediator subunits MED1 and MED24 cooperatively contribute to pubertal mammary gland development and growth of breast carcinoma cells.
abstract: The Mediator subunit MED1 is essential for mammary gland development and lactation, whose contribution through direct interaction with estrogen receptors (ERs) is restricted to involvement in pubertal mammary gland development and luminal cell differentiation. Here, we provide evidence that the MED24-containing submodule of Mediator functionally communicates specifically with MED1 in pubertal mammary gland development. Mammary glands from MED1/MED24 double heterozygous knockout mice showed profound retardation in ductal branching during puberty, while single haploinsufficient glands developed normally. DNA synthesis of both luminal and basal cells were impaired in double mutant mice, and the expression of ER-targeted genes encoding E2F1 and cyclin D1, which promote progression through the G(1)/S phase of the cell cycle, was attenuated. Luciferase reporter assays employing double mutant mouse embryonic fibroblasts showed selective impairment in ER functions. Various breast carcinoma cell lines expressed abundant amounts of MED1, MED24, and MED30, and attenuated expression of MED1 and MED24 in breast carcinoma cells led to attenuated DNA synthesis and growth. These results indicate functional communications between the MED1 subunit and the MED24-containing submodule that mediate estrogen receptor functions and growth of both normal mammary epithelial cells and breast carcinoma cells.
authors.affiliation: Laboratory of Hematology, Kobe University Graduate School of Health Sciences, Division of Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Hasegawa
authors.forename: Akiko
authors.initials: A
authors.lastname: Sumitomo
authors.forename: Azusa
authors.initials: A
authors.lastname: Fujita
authors.forename: Nami
authors.initials: N
authors.lastname: Aritome
authors.forename: Shumpei
authors.initials: S
authors.lastname: Mizuta
authors.forename: Keiji
authors.initials: K
authors.lastname: Matsui
authors.forename: Ruri
authors.initials: R
authors.lastname: Ishino
authors.forename: Kana
authors.initials: K
authors.lastname: Inoue
authors.forename: Norinaga
authors.initials: N
authors.lastname: Urahama
authors.forename: Junko
authors.initials: J
authors.lastname: Nose
authors.forename: Toru
authors.initials: T
authors.lastname: Mukohara
authors.forename: Shingo
authors.initials: S
authors.lastname: Kamoshida
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ito
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D006801:Humans; D008321:Mammary Glands, Animal / Q000196:embryology / Q000254:growth & development / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology; D056892:Mediator Complex / Q000378:metabolism*; D056913:Mediator Complex Subunit 1 / Q000378:metabolism*; D051379:Mice; D016196:S Phase
chemical_list: D050687:E2F1 Transcription Factor; C538855:MED1 protein, human; C503845:MED24 protein, human; C538856:Med1 protein, mouse; C121184:Med24 protein, mouse; D056892:Mediator Complex; D056913:Mediator Complex Subunit 1; D019938:Cyclin D1