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.
Highlights
Breast cancer is the leading cause of mortality in Hispanic and African-American women and the second most common cause of cancer-related death in Caucasian women
Treatment with the Growth hormone-releasing hormone (GHRH) antagonist MIA-602 at a dosage of 5 μg/day was initiated after the tumors reached a volume of ~100 ± 7 mm3 and lasted for five weeks
Much information has been accumulated concerning the role of GHRH, GH RH receptors, HCC1806 Control HCC1806 small interfering RNA (siRNA) MX-1 Control MX-1 siRNA
Summary
Breast cancer is the leading cause of mortality in Hispanic and African-American women and the second most common cause of cancer-related death in Caucasian women. In the United States alone, nearly 200,000 women are afflicted with breast cancer each year and 41,000 die as a result of their malignancy.[1] These figures can be extrapolated to approximately 4 million new cases and 820,000 deaths per year, worldwide. Breast cancer is a very heterogeneous disease and encompasses several distinct entities. The subtype defined as triple negative breast cancer (TNBC) is negative for estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2 (Her).
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