Antagonists of growth hormone-releasing hormone suppress in vivo tumor growth and gene expression in triple negative breast cancers
نویسندگان
چکیده
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.
منابع مشابه
Antagonistic analogs of growth hormone-releasing hormone increase the efficacy of treatment of triple negative breast cancer in nude mice with doxorubicin; A preclinical study
INTRODUCTION This study evaluated the effects of an antagonistic analog of growth hormone-releasing hormone, MIA-602, on tumor growth, response to doxorubicin, expression of drug resistance genes, and efflux pump function in human triple negative breast cancers. METHODS HCC1806 (doxorubicin-sensitive) and MX-1 (doxorubicin-resistant), cell lines were xenografted into nude mice and treated wit...
متن کاملThe Relationship Between Fibroblastic Growth Factor Receptor-1 (FGFR1) Gene Amplification in Triple Negative Breast Carcinomas and Clinicopathological Prognostic Factors
Background & Objective: In Triple-Negative Breast Cancers (TNBCs), estrogen receptor (ER), progesterone receptor (PR) and HER2/neu genes are not expressed. Fibroblastic Growth Factor Receptor-1 (FGFR1) gene product is a protein that acts as a receptor of thyrosin kinase. It plays a role in the proliferation, differentiation, and migration of malignant cells. The objective was t...
متن کاملTargeted chemotherapy for triple-negative breast cancers via LHRH receptor.
Triple-negative breast cancer does not express estrogen and progesterone receptors and there is no overexpression/amplification of the HER2-neu gene. Therefore, this subtype of breast cancer lacks the benefits of specific therapies which target these receptors. About 60% of all human breast cancers express receptors for luteinizing hormone releasing hormone (LHRH, GnRH), which might be used as ...
متن کاملComparison of Expression of Growth Hormone-Releasing Hormone and Its Receptor Splice Variant 1 in Different Stages of Endometriosis
متن کامل
Future of Triple Negative Breast Cancer: Can Immunotherapy Treat This Deadly Subtype of Breast Cancer?
Triple negative breast cancer (TNBC): challenges and solutions via the immune cells TNBC is one of the most complicated types of breast cancer to treat. It is generally diagnosed based on the absence of three receptors: estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) and is thus defined as a triple negative. TNBC is often more aggressive with lower survival rates...
متن کامل