Haploinsufficiency in the prometastasis Kiss1 receptor Gpr54 delays breast tumor initiation, progression, and lung metastasis.

Abstract

Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (Kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1R has been implicated in tumor angiogenesis and metastasis, but a broader evaluation of KISS1R in tumorigenesis and tumor progression is yet to be conducted. In this study, we used mouse models of Kiss1r gene knockout and mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT)-induced breast cancer to conduct such an evaluation. Kiss1r heterozygosity in MMTV-PyMT mice was sufficient to attenuate breast cancer initiation, growth, latency, multiplicity, and lung metastasis. To confirm these effects and assess possible contributions of endogenous ligands, we isolated primary tumor cells from PyMT/Kiss1r(+/+) and PyMT/Kiss1r(+/-) mice and compared their phenotypes by in vitro and in vivo assays. Kiss1r loss attenuated in vitro tumorigenic properties as well as tumor growth in vivo in immunocompromised NOD.SCID/NCr mice. Kiss1r activation in these cells, resulting from the addition of its ligand Kisspeptin-10, resulted in RhoA activation and RhoA-dependent gene expression through the Gαq-p63RhoGEF signaling pathway. Anchorage-independent growth was tightly linked to dose-dependent regulation of RhoA by Kiss1r. In support of these results, siRNA-mediated knockdown of KISS1R or inactivation of RhoA in human MCF10A breast epithelial cells overexpressing H-RasV12 was sufficient to reduce Ras-induced anchorage-independent growth. In summary, we concluded that Kiss1r attenuation was sufficient to delay breast tumor initiation, progression, and metastasis through inhibitory effects on the downstream Gαq-p63RhoGEF-RhoA signaling pathway.

• Authors: Sung-Gook Cho, Ying Wang, Melissa Rodriguez, Kunrong Tan, Wenzheng Zhang, Jian Luo, Dali Li, Mingyao Liu
• Journal: Cancer research (Cancer Res) Vol. 71 Issue 20 Pg. 6535-46 (Oct 15 2011) ISSN: 1538-7445 [Electronic] United States
• PMID: 21852382 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antigens, Polyomavirus Transforming
• KISS1 protein, human
• Kiss1r protein, mouse
• Kisspeptins
• Receptors, G-Protein-Coupled
• Receptors, Kisspeptin-1
• RhoA protein, mouse
• rho GTP-Binding Proteins
• rhoA GTP-Binding Protein

Topics

• Animals
• Antigens, Polyomavirus Transforming (genetics)
• Breast (metabolism)
• Cell Transformation, Neoplastic (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Haploinsufficiency
• Humans
• Kisspeptins (metabolism)
• Lung Neoplasms (genetics, secondary)
• Male
• Mammary Neoplasms, Animal (genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Mice, Transgenic
• Receptors, G-Protein-Coupled (genetics)
• Receptors, Kisspeptin-1
• rho GTP-Binding Proteins (metabolism)
• rhoA GTP-Binding Protein