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.