CCCM1, CCM2, CCM3 expressions in primary tumors and metastatic fields of mice breast cancer model

Objective: Sporadic or familial mutations in at least three genes, CCM1, CCM2, CCM3, cause Cerebral cavernous malformations (CCMs) which mostly occurs in the central nervous system. The precise functions of these genes are not fully understood. Studies show that the proteins are thought to have important roles on cell-cell junctions, migration, and apoptosis. All three proteins can be found in a same complex within the cell and they maintain stabilization of cell junctions. However; the role of CCM proteins on tumor development and metastasis has not been explained yet. Therefore, the aim of the study was to evaluate the expressions of CCM1, CCM2, CCM3 proteins in primary breast cancer tumor and highly metastatic organs lung and liver. Method: In our study; 4TLM, 4THM cell lines obtained from the metastasis of 4T1 (metastatic breast cancer cells) cells to liver, heart tissues were used. 4TLM, 4THM (500.000 cell/mouse) cells were injected to breast tissues of Balb/C female mice (8-10 weeks old) orthotopically. After 26 days, the primary tumors, liver and lung tissues were obtained and paraffin blocks were prepared. CCM1, CCM2 and CCM3 immunoreactions were evaluated by immunohistochemistry. All the findings were interpreted by comparing control animals that were not injected with tumor cells. Results: It was observed three CCM protein expressions in primary tumor tissues of all tumor injected animals. The expressions of CCM1 and CCM2 in lung and liver tissues were similar to the other. CCM2 expressions were vulnerable but, CCM3 had higher immunoreactivity in both groups. Interestingly, CCM proteins were not seen in metastatic tumor mass in liver tissues. But, CCM proteins were mainly observed in Kupffer cells and macrophages. Conclusion: The loss of CCM expressions in metastatic tissues and metastatic tumor mass which may change adherent junctions' stability, create it's own microenvironment and facilitate metastasis to distant organs. Therefore; CCM proteins might have a role new perspective of carcinogenesis.