Antagonists of GHRH decrease production of GH and IGF-I in MXT mouse mammary cancers and inhibit tumor growth.

Abstract

The involvement of IGF-I in mammary carcinogenesis is well established, but the role of GH, as an autocrine growth factor for breast cancers is poorly understood. The goal of our study was to investigate whether antagonists of GHRH can interfere with the effects of GH and IGF-I in MXT mouse mammary cancers. GHRH antagonists JV-1-36 and JV-1-38 inhibited growth of estrogen-independent MXT mouse mammary cancers in vivo, producing about 50% reduction in tumor volume (P < 0.05). This growth inhibition was associated with a decrease in cell proliferation and an increase in apoptosis in MXT cancers. RIA and RT- PCR analyses showed that the concentrations of GH and IGF-I and the levels of mRNA for GH and IGF-I in MXT tumors were reduced by the therapy with GHRH antagonists. Messenger RNA for GH receptors was also decreased. In vitro, the proliferation of MXT cancer cells was strongly stimulated by GH and less effectively by IGF-I, indicating that both GH and IGF-I may act as growth factors for this mammary carcinoma. GHRH antagonist JV-1-38 inhibited the autonomous growth of MXT cells and the proliferation induced by IGF-I or GH and diminished (3)H-thymidine-incorporation stimulated by IGF-I and GH. These findings and a sustained increase in cyclin B2 concentrations in the cells shown by immunoblotting indicate that JV-1-38 causes a block at the end of the G(2) phase of cell cycle. Our results demonstrate that GHRH antagonists decrease the local production of both GH and IGF-I in MXT mouse mammary cancers, the resulting growth inhibition being the consequence of reduced cell proliferation and increased apoptosis.