Molecular analyses of human breast cancer metastasis: genetic markers of progression
© Current Science Ltd 2000
Published: 12 March 2000
Breast tumorigenesis and metastasis result from an accumulation of genetic alterations involving 'cancer genes'. The prognostic value of these genetic alterations has been greatly investigated. However, few of them have been studied in secondary tumors, owing to the limited availability of surgical specimens. In human cancers, the genetic mechanisms underlying the metastatic process are still poorly understood. We investigated whether certain recurrent alterations could be associated with the metastatic process. We analysed the genetic profiles of primary tumors, local recurrences, and distant metastases of breast cancer. The alteration profiles in these 3 types of samples were different, suggesting distinct mechanisms of progression.
MYC, ERBB2 and CCND1 amplification is rare in distant metastases of breast cancer. These genetic amplifications could be involved in the genesis of primary tumors, but less in the later stages of breast cancer progression. In contrast, LOH is a frequent genetic event in breast cancer metastases. The LOH regions frequently observed in primary breast tumors are also detected in breast cancer metastases, mostly due to a clonal evolution of metastatic cells from the primary site to the metastases, but specific altered regions could also be acquired during metastatic progression. LOH analyses have defined regions of deletion associated with metastasis on several chromosomal regions, ie 3p21.3, 7q31, 15q14, 16q22.1 and 16q23.2. These regions contain several candidate metastasis suppressor genes such as DLC1, RPL14, DEF3, CTNNB1, MET, THBS1, CDH1. Other metastasis-related genes such as NME1 and KAI1 show losses of expression that do not correlate with LOH. Other genetic mechanisms could be involved. These studies could lead to the characterisation of new genomic markers of tumor aggressiveness and enhance our understanding of the molecular mechanisms of metastasis and cancer progression.