title: A Novel Effect of β-Adrenergic Receptor on Mammary Branching Morphogenesis and its Possible Implications in Breast Cancer.
abstract: Understanding the mechanisms that govern normal mammary gland development is crucial to the comprehension of breast cancer etiology. β-adrenergic receptors (β-AR) are targets of endogenous catecholamines such as epinephrine that have gained importance in the context of cancer biology. Differences in β2-AR expression levels may be responsible for the effects of epinephrine on tumor vs non-tumorigenic breast cell lines, the latter expressing higher levels of β2-AR. To study regulation of the breast cell phenotype by β2-AR, we over-expressed β2-AR in MCF-7 breast cancer cells and knocked-down the receptor in non-tumorigenic MCF-10A breast cells. In MCF-10A cells having knocked-down β2-AR, epinephrine increased cell proliferation and migration, similar to the response by tumor cells. In contrast, in MCF-7 cells overexpressing the β2-AR, epinephrine decreased cell proliferation and migration and increased adhesion, mimicking the response of the non-tumorigenic MCF-10A cells, thus underscoring that β2-AR expression level is a key player in cell behavior. β-adrenergic stimulation with isoproterenol induced differentiation of breast cells growing in 3-dimension cell culture, and also the branching of murine mammary epithelium in vivo. Branching induced by isoproterenol was abolished in fulvestrant or tamoxifen-treated mice, demonstrating that the effect of β-adrenergic stimulation on branching is dependent on the estrogen receptor (ER). An ER-independent effect of isoproterenol on lumen architecture was nonetheless found. Isoproterenol significantly increased the expression of ERα, Ephrine-B1 and fibroblast growth factors in the mammary glands of mice, and in MCF-10A cells. In a poorly differentiated murine ductal carcinoma, isoproterenol also decreased tumor growth and induced tumor differentiation. This study highlights that catecholamines, through β-AR activation, seem to be involved in mammary gland development, inducing mature duct formation. Additionally, this differentiating effect could be resourceful in a breast tumor context.
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, CABA, Argentina.
authors.forename: Lucía
authors.initials: L
authors.lastname: Gargiulo
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, CABA, Argentina.
authors.forename: María
authors.initials: M
authors.lastname: May
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, CABA, Argentina.
authors.forename: Ezequiel M
authors.initials: EM
authors.lastname: Rivero
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, CABA, Argentina.|Laboratorio de Farmacología de Receptores, Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 1113, Buenos Aires, CABA, Argentina.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Copsel
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, CABA, Argentina.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lamb
authors.affiliation: Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lydon
authors.affiliation: Laboratorio de Farmacología de Receptores, Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 1113, Buenos Aires, CABA, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Davio
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, CABA, Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanari
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, CABA, Argentina.
authors.forename: Isabel A
authors.initials: IA
authors.lastname: Lüthy
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), CONICET-Universidad Nacional del Sur, Camino La Carrindanga km 7, 8000, Bahía Blanca, Argentina. abruzzone@inibibb-conicet.gov.ar.
authors.forename: Ariana
authors.identifier: 0000-0002-5511-2021
authors.initials: A
authors.lastname: Bruzzone
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000187:drug effects / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D004967:Estrogens; D018343:Receptors, Adrenergic, beta-2; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D007545:Isoproterenol
keywords: Beta-adrenergic receptor; Breast cancer; Estrogen receptor; Mammary gland development; Non-tumorigenic breast epithelial cells; Normal mammary gland