α2-Adrenoceptors Enhance Cell Proliferation and Mammary Tumor Growth Acting Through both the Stroma and the Tumor Cells

Author(s): A. Bruzzone , C. Perez Pinero , P. Rojas , M. Romanato , H. Gass , C. Lanari , I. A. Luthy .

Journal Name: Current Cancer Drug Targets

Volume 11 , Issue 6 , 2011

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Abstract:

We have previously described enhanced human breast cancer cell proliferation and mouse mammary tumor growth induced by α2-adrenergic agonists, associated with α2-adrenoceptor (α2-AR) expression in epithelial cells. The aim of the present work was to assess if stromal fibroblasts can contribute to this effect. α2-AR expression was assessed by immunocytochemistry and immunohistochemistry, cell proliferation by [3H]- Thymidine incorporation and tumor growth by measuring with caliper. All tested mouse and human fibroblasts expressed at least two α2-AR subtypes and α2-adrenergic agonists enhanced fibroblast proliferation. In vivo, the α2-adrenergic agonist clonidine significantly enhanced tumor growth. The α2- adrenergic antagonist rauwolscine reversed this effect, but when administered alone, significantly inhibited tumor growth. Clonidine significantly stimulated cell proliferation in the epithelial-enriched fraction, the cancer associated fibroblastenriched fraction and the co-culture of both fractions in primary cultures from both tumors (IBH-4 and IBH-6). Rauwolscine reversed clonidine stimulation in every fraction. However, when incubated alone, the inhibitory effect was observed in fractions from IBH-4 tumors but not from IBH-6 tumors. These experiments show that fibroblasts from tumor stroma are also influenced by α2-adrenergic compounds through the α2-ARs expressed in these cells. Moreover, the α2-adrenergic antagonist rauwolscine could eventually block in both epithelial and stromal cells, the mitogenic effect of catecholamines released during stress, providing a potential additional treatment for breast cancer patients. Chemists synthesizing adrenergic compounds should consider their action in breast cancer patients.

Keywords: Clonidine, rauwolscine, adrenoceptors, mammary tumor, carcinoma-associated fibroblasts, breast cancer, fibroblast MC4-L4F, Dexmedetomidine, G protein coupled receptors, Dulbecco's modified Eagle's medium

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Article Details

VOLUME: 11
ISSUE: 6
Year: 2011
Page: [763 - 774]
Pages: 12
DOI: 10.2174/156800911796191051
Price: $58

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