GH Action in Prostate Cancer Cells Promotes Proliferation, Limits Apoptosis, and Regulates Cancer-related Gene Expression.

Previous studies investigating the effects of blocking the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in prostate cancer found no effects of the growth hormone receptor (GHR) antagonist, pegvisomant, on the growth of grafted human prostate cancer cells in vivo. However, human GHR is not activated by mouse GH, so direct actions of GH on prostate cancer cells were not evaluated in this context. The present study addresses the species specificity of GH-GHR activity by investigating GH actions in prostate cancer cell lines derived from a mouse Pten-deletion model. In vitro cell growth was stimulated by GH and reduced by pegvisomant. These in vitro GH effects were mediated at least in part by the activation of JAK2 and STAT5. When Pten-mutant cells were grown as xenografts in mice, pegvisomant treatment dramatically reduced xenograft size, and this was accompanied by decreased proliferation and increased apoptosis. RNA sequencing of xenografts identified 1765 genes upregulated and 953 genes downregulated in response to pegvisomant, including many genes previously implicated as cancer drivers. Further evaluation of a selected subset of these genes via quantitative reverse transcription-polymerase chain reaction determined that some genes exhibited similar regulation by pegvisomant in prostate cancer cells whether treatment was in vivo or in vitro, indicating direct regulation by GH via GHR activation in prostate cancer cells, whereas other genes responded to pegvisomant only in vivo, suggesting indirect regulation by pegvisomant effects on the host endocrine environment. Similar results were observed for a prostate cancer cell line derived from the mouse transgenic adenocarcinoma of the mouse prostate (TRAMP) model.

Mammary Tumors Growing in the Absence of Growth Hormone Are More Sensitive to Doxorubicin Than Wild-Type Tumors.

Previously, we reported that N-methyl-N-nitrosourea (MNU)-induced mammary tumors could be established in mutant spontaneous dwarf rats (SDRs), which lack endogenous growth hormone (GH) by supplementing with exogenous GH, and almost all such tumors regressed upon GH withdrawal. When the highly inbred SDR line was outcrossed to wild-type (WT) Sprague-Dawley rats, MNU-induced mammary tumors could still be established in resulting outbred SDRs by supplementing with exogenous GH. However, unlike tumors in inbred SDRs, 65% of mammary tumors established in outbred SDRs continued growth after GH withdrawal. We further tested whether these tumors were more sensitive to doxorubicin than their WT counterparts. To accomplish this, MNU-induced mammary tumors were established in WT rats and in SDRs supplemented with exogenous GH. Once mammary tumors reached 1 cm3 in size, exogenous GH was withdrawn from SDRs, and the subset that harbored tumors that continued or resumed growth in the absence of GH were selected for doxorubicin treatment. Doxorubicin was then administered in 6 injections over 2 weeks at 2.5 mg/kg or 1.25 mg/kg for both the WT and SDR groups. The SDR mammary tumors that had been growing in the absence of GH regressed at both doxorubicin doses while WT tumors continued to grow robustly. The regression of SDR mammary tumors treated with 1.25 mg/kg doxorubicin was accompanied by reduced proliferation and dramatically higher apoptosis relative to the WT mammary tumors treated with 1.25 mg/kg doxorubicin. These data suggest that downregulating GH signaling may decrease the doxorubicin dose necessary to effectively treat breast cancer.