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Loss of Heterozygosity Events Impeding Breast Cancer Metastasis Contain the MTA1 Gene¹

Breast Center [M. D. M., C. K. O., S. K. M., D. C. A., P. O.], Departments of Molecular and Cellular Biology [M. D. M., P. O.], Medicine [C. K. O.], and Pathology [S. K. M., D. C. A.], Baylor College of Medicine, Houston, Texas 77030, and Department of Life Sciences, University of Texas at San Antonio, San Antonio, Texas 78249 [K. F.]

Breast cancer mortality is seldom attributable to the primary tumor, but rather to the presence of systemic (metastatic) disease. Axillary lymph node dissection can identify the presence of metastatic breast cancer cells and serves as a marker for systemic disease. Previous work in our laboratory determined that rates of loss of heterozygosity (LOH) of a 1.6-Mb region of chromosome 14q 31.2 is much higher in axillary lymph node-negative primary breast tumors than in axillary lymph node-positive primary breast tumors (P. O’Connell et al., J. Natl. Cancer Inst., 91: 1391–1397, 1999.). This unusual observation suggests that, whereas the LOH of this region promotes primary breast cancer formation, some gene(s) mapping to this 1.6-Mb region is rate-limiting for breast cancer metastasis. Thus, if primary breast cancers delete this region, their ability to metastasize decreases. To identify this gene(s), we have physically mapped this area of chromosome 14q, confirmed the position of two known genes and 13 other expressed sequence tags into this 1.6-Mb region. One of these, the metastasis-associated 1 (MTA1) gene, previously identified as a metastasis-promoting gene (Y. Toh et al., J. Biol. Chem., 269: 22958–22963, 1994.), mapped to the center of our 1.6-Mb target region. Thus, MTA1 represents a strong candidate for this breast cancer metastasis-promoting gene.