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

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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.

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Acknowledgements

In the memory of our friend Hervé Paris. We gratefully thank Federico Carrizo from Laboratorios Beta and Denver Farma Argentina for kindly providing insulin and Michel Bouvier from Département de Biochimie, Université de Montréal for kindly providing β2-AR plasmid. Thanks are also due to KLM for fulvestrant and Bruno Luna and Anita Sahores for their technical help. Authors declare there are no conflicts of interest. This work was supported by a grant from PICT N° 103 (ANPCyT), INC and PIP N° 539 from CONICET, Fundación René Barón and Fundación Roemmers.

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Authors and Affiliations

  1. Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, CABA, Argentina

    Lucía Gargiulo, María May, Ezequiel M. Rivero, Sabrina Copsel, Caroline Lamb, Claudia Lanari & Isabel A. Lüthy

  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

    Sabrina Copsel & Carlos Davio

  3. Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    John Lydon

  4. Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), CONICET-Universidad Nacional del Sur, Camino La Carrindanga km 7, 8000, Bahía Blanca, Argentina

    Ariana Bruzzone

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  1. Lucía Gargiulo
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  2. María May
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  3. Ezequiel M. Rivero
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  7. Carlos Davio
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  9. Isabel A. Lüthy
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  10. Ariana Bruzzone
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Correspondence to Ariana Bruzzone.

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Gargiulo, L., May, M., Rivero, E.M. et al. A Novel Effect of β-Adrenergic Receptor on Mammary Branching Morphogenesis and its Possible Implications in Breast Cancer. J Mammary Gland Biol Neoplasia 22, 43–57 (2017). https://doi.org/10.1007/s10911-017-9371-1

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