Transcriptional programs induced by c-Myb prevent lung seeding of mammary tumors
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| Year of publication | 2014 |
| Type | Conference abstract |
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| Description | Metastasis is the cause of most cancer-related deaths. Overt metastasis is the end result of a multistep process that involves dissemination of tumor cells to distant organs and subsequent adaptation to foreign tissue microenvironments. Success in distant colonization is dictated by both intrinsic characteristics of tumor cells and the permissive/restrictive conditions in secondary tissue. By repeated challenge of 4T1 mammary carcinoma cells with lung microenvironment in vivo, we selected cells highly productive in short-term lung seeding. To search for molecular mechanisms responsible for seeding of tumor cells in the lungs we analyzed expression of the candidate proteins and discovered significant down-regulation of the c-Myb transcription factor in the selected cells. We documented previously that deregulation of c-Myb in mammary tumors results in altered metastasis pattern in mice: the Myb-overexpressing tumors generated liver and bone metastases, while control tumors spread spontaneously to liver, bone and lung. Here we demonstrated that Myb overexpression in 4T1 cells attenuated the lung seeding upon intravenous injection. This implies that c-Myb might be critical for early steps of metastatic colonization of the lungs. The early events occurring in the metastatic site include arrest of tumor cells in the endothelium, extravasation and survival in a hostile microenvironment. Specific features of endothelium and vascular permeabilization in lung, compared to liver and bone marrow, prompted us to test whether c-Myb affects transendothelial migration (TEM) of mammary cancer cells. The interaction of 4T1 cells with different types of endothelial cells was monitored by impedance-based cell analyzer or microscopy in transwell set-up, as well as imaged on the 3D matrix by confocal microscope. We demonstrated that c-Myb slightly reduced transmigration of 4T1 cells through endothelium. Analysis of publically available microarray data revealed that breast cancer cell lines capable of TEM (TEM+) express lower amounts of MYB mRNA than TEM- cell lines. In addition, pulmonary metastases of human breast carcinoma exhibit lower MYB expression than extra-pulmonary metastases (Oncomine). We hypothesize that c-Myb-induced transcriptional programs alter tumor-stroma interactions at the metastatic site in an organ-specific manner. |
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