GHRH, in addition to stimulating the release of
growth hormone (GH) from the pituitary, is a trophic factor for pituitary somatotrophs.
Growth hormone-releasing hormone is also expressed in the gonads, gastrointestinal tract, pancreas, thymus, and lymphocytes, as well as in
tumors of the pancreas, lung, central nervous system, and breast. Since GHRH has mitogenic effects, we examined the hypothesis that GHRH is an autocrine/paracrine
growth factor in neoplastic breast tissue. The effect of disrupting endogenous GHRH on cell growth and apoptosis of MDA231 cells was examined through the use of a competitive GHRH antagonist, [N-acetyl-Tyr1, D-Arg2] fragment 1-29Amide (
GHRHa). Cell proliferation was determined by direct cell counting and tritiated
thymidine incorporation. Apoptosis was analyzed by examination of
DNA laddering and nuclear condensation.
GHRHa resulted in a dose-dependent, transient, and reversible decrease in cell number, proliferation rate, and tritiated
thymidine uptake. Conversely,
GHRHa led to a marked and dose-dependent increase in both
DNA laddering and nuclear condensation. These results indicate that disruption of endogenous GHRH action in MDA231 cells results in both decreased cellular proliferation and increased apoptosis. Taken together, the findings suggest that endogenous GHRH acts as an autocrine/paracrine factor in the regulation of growth of at least some
breast cancer cell types.