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

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.