Genomic Alterations Associated with Early Stages of Breast Tumor Metastasis
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Molecular studies suggest that acquisition of metastatic potential occurs early in the development of breast cancer; mechanisms by which cells disseminate from the primary carcinomas and successfully colonize foreign tissues are, however, largely unknown. Thus, we examined levels and patterns of chromosomal alterations in primary breast tumors from node-negative (n = 114) and node-positive (n = 115) patients to determine whether specific genomic changes are associated with tumor metastasis.
Fifty-two genetic markers representing 26 chromosomal regions commonly altered in breast cancer were examined in laser microdissected tumor samples to assess levels and patterns of allelic imbalance (AI). Real time-PCR (RT-PCR) was performed to determine expression levels of candidate genes. Data was analyzed using exact unconditional and Student’s t-tests with significance values of P < 0.05 and P < 0.002 used for the clinicopathological and genomic analyses, respectively.
Overall levels of AI in primary breast tumors from node-negative (20.8%) and node-positive (21.9%) patients did not differ significantly (P = 0.291). When data were examined by chromosomal region, only chromosome 8q24 showed significantly higher levels (P < 0.0005) of AI in node-positive primary tumors (23%) versus node-negative samples (6%). c-MYC showed significantly higher levels of gene expression in primary breast tumors from patients with lymph node metastasis.
Higher frequencies of AI at chromosome 8q24 in patients with positive lymph nodes suggest that genetic changes in this region are important to the process of metastasis. Because overexpression of c-MYC has been associated with cellular dissemination as well as development of the premetastatic niche, alterations of the 8q24 region, including c-MYC, may be key determinants in the development of lymph node metastasis.
KeywordsAllelic imbalance Primary breast tumor Metastasis
Presented in part at the Society of Surgical Oncology’s 61st Annual Cancer Symposium, March 13—16, 2008 in Chicago, IL. This work was performed under the auspices of the Clinical Breast Care Project, a joint effort of many investigators and staff members whose contributions are gratefully acknowledged. We especially thank the program participants. Supported by the United States Department of Defense (Military Molecular Medicine Initiative MDA W81XWH-05–2–0075). The opinion and assertions contained herein are the private views of the authors and are not to be construed as official or as representing the views of the Department of the Army or the Department of Defense.
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