GHRH Antagonist MZ-J-7-118 Inhibits Triple-Negative Breast Cancer Growth via Autocrine GHRH Loop
Background
Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor, progesterone receptor, and HER2 overexpression, leaving chemotherapy as the sole standard-of-care option and conferring an unfavorable prognosis. Unlike hormone-receptor-positive subtypes, TNBC cannot be targeted with endocrine therapies or HER2-directed agents, creating a critical therapeutic gap. Growth hormone-releasing hormone (GHRH) and its receptor (GHRH-R) have been implicated in paracrine/autocrine tumor growth across multiple cancer types, with GHRH antagonists demonstrating inhibitory activity in diverse malignancies. The functional splice variant SV1 of the GHRH-R has been identified as a key mediator of these effects in peripheral tissues and cancers. Whether TNBC expresses the molecular machinery for GHRH-driven autocrine signaling had not been established prior to this work.
Study Design
Investigators screened human TNBC tissue specimens for mRNA expression of GHRH, GHRH-R, and splice variant SV1 using qPCR-based methods. Two human TNBC cell lines — HCC1806 and HCC1937 — were tested for SV1 protein expression by immunoreaction. In HCC1806 cells (SV1-positive), proliferative responses to GHRH(1-44)NH₂ and growth-inhibitory responses to GHRH antagonist MZ-J-7-118 were evaluated in vitro. Activation of MAP-kinase signaling (ERK-1/2) downstream of GHRH receptor engagement was also assessed in HCC1806 as a mechanistic endpoint. HCC1937 (SV1-negative) served as a receptor-negative comparator line.
Results
GHRH mRNA was detected in 80% of human TNBC tissue samples. The full-length GHRH-R was expressed in 25% of specimens, while the functional splice variant SV1 was expressed in 70% of specimens — nearly three times the rate of the canonical receptor. Immunoreactive SV1 protein was confirmed in HCC1806 cells but was absent in HCC1937, establishing receptor-defined cell-line heterogeneity within TNBC.
GHRH(1-44)NH₂ stimulated growth of HCC1806 cells while GHRH antagonist MZ-J-7-118 inhibited growth of the same line, directly demonstrating a functional, druggable autocrine loop in a TNBC cell model.
In HCC1806, GHRH also activated MAP-kinase pathway components ERK-1/2, providing a molecular mechanism linking SV1 receptor engagement to a canonical proliferative signaling cascade. Together, the co-expression of ligand and receptor in 80% and 70% of tumors, respectively, is consistent with a self-sustaining autocrine/paracrine growth loop operative in the majority of TNBC specimens examined.
Key Findings
- GHRH mRNA detected in 80% of human TNBC tissue specimens examined.
- Functional splice variant SV1 of GHRH-R expressed in 70% of TNBC samples vs. 25% for full-length receptor.
- GHRH(1-44)NH₂ stimulated HCC1806 cell growth; GHRH antagonist MZ-J-7-118 inhibited it.
- ERK-1/2 MAP-kinases activated by GHRH in SV1-positive HCC1806 cells.
- HCC1937 cells were SV1-negative and served as receptor-absent comparator.
Why It Matters
TNBC patients currently have no approved targeted therapy, making every mechanistically distinct druggable axis clinically meaningful. The finding that SV1 — not the canonical GHRH-R — dominates receptor expression in 70% of tumors positions SV1-selective antagonists as a rational drug class for this indication. GHRH antagonists like MZ-J-7-118 could represent a non-chemotherapy option if in vivo efficacy is confirmed, potentially opening combination strategies alongside existing cytotoxics. For clinicians and translational researchers, the co-expression of ligand and receptor in the majority of primary tumor specimens supports patient-selection biomarker strategies built on SV1 immunohistochemistry. The data remain preclinical and in vitro; no dosing, safety, or pharmacokinetic parameters in humans can yet be drawn from this work.
