Antagonists of growth hormone-releasing hormone suppress in vivo tumor growth and gene expression in triple negative breast cancers

Abstract

This study evaluated the effects of a modern antagonistic analog of GHRH on tumor growth and on expression of inflammatory cytokine genes in two models of human triple negative breast cancers (TNBC). The TNBC subtype is refractory to the treatment options available for other hormone-independent breast cancers. Inflammatory cytokines play a major role in the cellular signaling associated with breast cancer pathogenesis and enhance epithelial-mesenchymal transitions (EMT), drug resistance, and metastatic potential. Growth hormone-releasing hormone (GHRH) is a hypothalamic neuropeptide which regulates the synthesis and release of growth hormone by the pituitary and is an autocrine/paracrine growth factor for multiple human cancers. The effects of analogs of GHRH on tumoral cytokine expression have not been previously investigated. Animals bearing xenografts of the human TNBC cell lines, HCC1806 and MX-1, were treated with MIA-602, an antagonistic analog of GHRH. Treatment with MIA-602 significantly reduced tumor growth. We quantified transcript levels of the genes for several inflammatory cytokines. Expression of INFγ, IL-1α, IL-4, IL-6, IL-8, IL-10, and TNFα, was significantly reduced by treatment with MIA-602. We conclude that treatment of TNBC with GHRH antagonists reduces tumor growth through an action mediated by tumoral GHRH receptors and produces a suppression of inflammatory cytokine signaling. Silencing of GHRH receptors in vitro with siRNA inhibited the expression of GHRH-R genes and inflammatory cytokine genes in HCC1806 and MX-1 cells. Further studies on GHRH antagonists may facilitate the development of new strategies for the treatment of resistant cancers.

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

“…Although the presence of GHRH-R has been previously identified in multiple types of human cancers (11)(12)(13)(14)(15)(16)(17)(18)(19), the clinical importance of GHRH-R in the tumorigenic progression and patient outcome was unappreciated prior to this study. In this study, by analyzing multiple cohorts of GC patients of different races, we defined the heretofore undocumented associations between GHRH-R and poor survival of human GC.…”

“…( [11][12][13][14][15][16][17][18][19]. The GHRH/GHRH-R pathway is considered a growth factor-signaling pathway in these cancers and may modulate the activities of multiple intracellular pathways (11)(12)(13).…”

“…Thus, targeting the GHRH/GHRH-R pathway has been proposed for the treatment of cancer (11,12). Over the past three decades, various classes of GHRH-R antagonists have been developed that have shown strong growth-inhibitory effects in cancer both in vitro and in vivo (11)(12)(13)(14)20). represents the latest in a series of GHRH-R antagonists and has been chosen for clinical development.…”

Antagonists of growth hormone-releasing hormone inhibit proliferation induced by inflammation in prostatic epithelial cells

“…Anti-inflammatory effects for GHRH antagonists were also demonstrated in experimental models of cancer and ocular inflammation (39,40).…”

Novel GHRH antagonists suppress the growth of human malignant melanoma by restoring nuclear p27 function

“…22 We have shown previously that GHRH antagonists inhibit the growth of diverse human tumors xenografted into nude mice. [23][24][25][26][27][28][29][30] Many of these published studies reported the effects of early-stage GHRH antagonists that were later considered unsuitable for clinical development due to limited stability or low potency. In our initial studies with melanomas, for example, early GHRH antagonists MZ-5-156, MZ-7-138 and JMR-132 were shown to inhibit growth of MRI-H187, MRI-H255 and A375 human melanoma cell lines xenografted into nude mice.…”