Alpha2-Adrenoceptors Enhance Cell Proliferation and Mammary Tumor

BRUZZONE A; PEREZ PIÑERO C; ROJAS P; ROMANATO M; GASS H; LANARI C; LUTHY IA

CURRENT CANCER DRUG TARGETS

BENTHAM SCIENCE PUBL LTD

Lugar: Londres; Año: 2011 vol. 11 p. 763 - 774

1568-0096

We have previously described enhanced human breast cancer cell proliferation and mouse mammary tumor growth induced by alpha2-adrenoceptor (alpha2-AR) expression in epithelial cells. The aim of the present work was to assess if stromal fibroblasts can contribute to this effect. Alpha2-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 alpha2-AR subtypes and alpha2-adrenergic agonists enhanced fibroblast proliferation. In vivo, the alpha2-adrenergic agonist clonidine significantly enhanced tumor growth. The alpha2-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 alpha2-adrenergic compounds through the alpha2-ARs expressed in these cells. Moreover, the alpha2-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.