Tissue-specific metastases

Breast cancer is the most frequently diagnosed cancer in women in Europe and the United States, with an estimated 608,380 new cases of invasive disease in 2007 1,2. The majority of these patients died due to the tumor metastatic spread. Our current understanding of the biology of breast cancer is a major barrier to identify novel therapies and improve existing therapies for the treatment and prevention of this disease. Breast cancer is a remarkably heterogeneous disease, but subsets of tumors show recurrent patterns of transcriptional, genomic, and biological abnormality. Understanding how genes in these “patterns” collectively function in an otherwise heterogeneous biological setting to enable progression and modulate response to therapy is critical to improve management of the disease. In particular, we are interested in understanding how ER pathway contributes in leading molecular events in breast cancer metastasis. The predisposition of primary tumors to selectively invade different organs has been long recognized 3. Recent work has functionally identified and clinically validated sets of genes whose overexpression in ER-negative breast cancer and prostate cells confers a selective advantage for the colonization of bones4,5 or lungs6. The ability to subsequently colonize distant organs depends on the organ-colonizing faculties of disseminated tumor cells as well as on certain requirements that may be present in the otherwise restrictive microenvironment of target organs7. Our work focuses on breast cancer metastatic suppressor genes and their functions in the metastatic process. For this, we are using breast cancer cell line model and their derivatives, which have a strong metastatic capacity to lung and bone. We used these subpopulations to functionally validate a particular metastasis suppressor whose loss of expression in ER- breast cancer cells confers a selective advantage for the colonization of lung. Tumor cells under certain conditions cannot grow or survive in the absence of a supportive microenvironment. Indeed, the microenvironment may even drive tumor and metastasis development by selecting for highly invasive and resistant cancer cell phenotypes and systemically fostering the mobilization of marrow-derived progenitor cell. In particular, loss of expression of our gene of interest is selected in the primary tumor. Interestingly, how these particular gene controls the ability to subsequently colonize distant organs depends on the organ-colonizing faculties of disseminated tumor cells rather than interaction with the restrictive microenvironment of target organs. Collectively, these results show that genes selected for metastasis contribute to the different steps and represent the random accumulation of traits that provide the necessary advantage for adaptation to a different organ microenvironment and need at any time. 1. American_Cancer_Society. Cancer facts and figures. American Cancer Society (2007). 2. Ferlay, J., et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18, 581-592 (2007). 3. Paget, S. The dstribuition of secondary growths in cancer of the breast. Lancet 1, 571-573 (1889). 4. Kang, Y., et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3, 537-549 (2003). 5. Lynch, C.C., et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7, 485-496 (2005). 6. Minn, A.J., et al. Genes that mediate breast cancer metastasis to lung. Nature 436, 518-524 (2005). 7. Gupta, G.P. & Massague, J. Cancer metastasis: building a framework. Cell 127, 679-695 (2006).