GnRH analogs reduce invasiveness of human breast cancer cells.
OBJECTIVE
Bone, besides lung and liver, is one of the most preferential metastatic target sites for breast cancers. Although the precise molecular mechanisms underlying this preference need to be elucidated, it appears that bone microenvironments possess unique biological features that enable circulating cancer cells to home, survive and proliferate, and destroy bone. The majority of human breast cancers and in addition most breast cancer cell lines express GnRH receptors. Their proliferation is time- and dose-dependently reduced by GnRH-I and GnRH-II agonists by counteracting of the mitogenic signal transduction.


METHODS
We have established a coculture system of different breast cancer cell lines stable transfected with red fluorescence (DS-Red) and human primary osteoblasts (hOB) or MG63 human osteosarcoma cells to analyze tumor cell invasion to bone.


RESULTS
We could show that breast cancer cell invasion was increased when cocultured with hOB or MG63. Treatment with GnRH-I and GnRH-II analogs reduced the ability to invade a reconstituted basement membrane (Matrigel) and to migrate in response to the cellular stimulus. Searching for the molecular mechanisms we found that GnRH treatment reduces expression of the osteoblast derived chemokine SDF-1 by hOB or MG63 cells cocultured with breast cancer cells.


CONCLUSIONS
These data represent the first report that the activation of tumor GnRH receptors reduces the metastatic potential of breast cancer cells. The crosstalk between metastatic breast cancer cells and bone is critical to the development and progression of bone metastases. Disruption of this interaction will allow us to design mechanism-based effective and specific therapeutic interventions for bone metastases.
von Alten
Julia
J
Department of Gynecology and Obstetrics, Georg-August-University, Robert-Koch-Street 40, D-37075 Göttingen, Germany.
Fister
Stefanie
S
Schulz
Hiltrud
H
Viereck
Volker
V
Frosch
Karl-Heinz
KH
Emons
Günter
G
Gründker
Carsten
C
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis
D000970:Antineoplastic Agents; D007987:Gonadotropin-Releasing Hormone