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J Mammary Gland Biol Neoplasia. 2017 Mar;22(1):43-57. doi: 10.1007/s10911-017-9371-1. Epub 2017 Jan 11.

A Novel Effect of β-Adrenergic Receptor on Mammary Branching Morphogenesis and its Possible Implications in Breast Cancer.

Author information

1
Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, CABA, Argentina.
2
Laboratorio de Farmacología de Receptores, Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 1113, Buenos Aires, CABA, Argentina.
3
Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
4
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.

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.

KEYWORDS:

Beta-adrenergic receptor; Breast cancer; Estrogen receptor; Mammary gland development; Non-tumorigenic breast epithelial cells; Normal mammary gland

PMID:
28074314
DOI:
10.1007/s10911-017-9371-1
[Indexed for MEDLINE]

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