α(2)-Adrenoceptors enhance cell proliferation and mammary tumor growth acting through both the stroma and the tumor cells

• Published in: Current cancer drug targets Vol. 11; no. 6; p. 763
• Main Authors: Bruzzone, Ariana, Piñero, Cecilia Pérez, Rojas, Paola, Romanato, Marina, Gass, Hugo, Lanari, Claudia, Lüthy, Isabel A
• Format: Journal Article
• Language: English
• Published: Netherlands 01-07-2011
• Subjects: Adrenergic alpha-2 Receptor Agonists - pharmacology; Adrenergic alpha-2 Receptor Antagonists - pharmacology; Animals; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Catecholamines - pharmacology; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Clonidine - pharmacology; Disease Progression; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; Immunohistochemistry; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; Receptors, Adrenergic, alpha-2 - metabolism; Stromal Cells - drug effects; Stromal Cells - metabolism; Stromal Cells - pathology; Yohimbine - pharmacology
• ISSN: 1873-5576

We have previously described enhanced human breast cancer cell proliferation and mouse mammary tumor growth induced by α(2)-adrenoceptor (α(2)-AR) expression in epithelial cells. The aim of the present work was to assess if stromal fibroblasts can contribute to this effect. α(2)-AR expression was assessed by immunocytochemistry and immunohistochemistry, cell proliferation by [(3)H]-Thymidine incorporation and tumor growth by measuring with caliper. All tested mouse and human fibroblasts expressed at least two α(2)-AR subtypes and α(2)-adrenergic agonists enhanced fibroblast proliferation. In vivo, the α(2)-adrenergic agonist clonidine significantly enhanced tumor growth. The α(2)-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 fibroblast-enriched 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 α(2)-adrenergic compounds through the α(2)-ARs expressed in these cells. Moreover, the α(2)-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.