Gene expression profiles of primary breast tumors maintained in distant metastases

Abstract

It has been debated for decades how cancer cells acquire metastatic capability. It is unclear whether metastases are derived from distinct subpopulations of tumor cells within the primary site with higher metastatic potential, or whether they originate from a random fraction of tumor cells. Here we show, by gene expression profiling, that human primary breast tumors are strikingly similar to the distant metastases of the same patient. Unsupervised hierarchical clustering, multidimensional scaling, and permutation testing, as well as the comparison of significantly expressed genes within a pair, reveal their genetic similarity. Our findings suggest that metastatic capability in breast cancer is an inherent feature and is not based on clonal selection.M etastases are the main cause of death in breast cancer.They arise, after the spread of cells from a primary tumor via the blood circulation, as solid tumors in distant organs (1, 2). The prevailing model of metastasis suggests that metastatic capacity is acquired late in tumorigenesis and is a nonrandom and highly selective process (3,4). This genetic selection model, based on in vitro culturing of tumor cell lines subsequently transplanted into mice, encompasses the escape, survival, and proliferation of a cryptic minority of tumor cells from subpopulations with increased metastatic capacity in the primary site (3-6). Such a model implies that a metastasis arising from a selected subclone would be molecularly distinct from its primary tumor. The subpopulation concept by Fidler is widely accepted, although the metastatic process has also been described as a stochastic event, giving primary tumor cells an equal metastatic potential (7-9).It has been shown that activation of a single gene, which in turn affects a process essential for metastasis, can be sufficient for inducing metastasis in vitro (10,11). This would imply that one gene, when activated early in its development, can empower the metastatic process once a primary tumor with additional genetic changes has been established. In human breast cancer, it has recently been shown that expression profiles can predict the risk of development of distant metastases even for small primary tumors (12, 13). These findings suggest that the capacity to metastasize might be acquired relatively early in multistep tumorigenesis (14), thereby challenging the subpopulation concept. If this inherent model is correct, a metastasis might then be genetically similar, if not identical, to that of the primary tumor from which it originated. To test this hypothesis, we compared pairs of human primary breast carcinomas and their metastases, developed years later at distant sites, by gene expression profiling. Materials and MethodsBreast Tumors and Metastases. Tumor samples from breast cancer patients with a surgically removed distant metastasis were selected from the fresh-frozen tissue bank of the Netherlands Cancer Institute. The tumor and metastatic material was snapfrozen in liquid nitrogen within 1 h after surgery. Before and af...

HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management?

“…The gene expression profile of metastasis and their primaries has also been compared and has been shown to cluster together (Ramaswamy et al, 2003;Weigelt et al, 2003). In the literature, Cyclin D1 amplification in primary breast tumours ranged between 10 and 23%.…”

The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer

“…RNA extraction and gene expression analysis RNA isolation and amplification were performed as previously described [17]. One 5-lm tissue section of the biopsy was hematoxylin and eosin stained to monitor the tumor cell percentage of the tissue.…”

TRAF4 overexpression is a common characteristic of human carcinomas

“…This suggests that TRAF4 upregulation is more likely gained at an early stage of tumorigenesis rather than being acquired during cancer progression. Accordingly, gene expression profiles of primary breast carcinomas have revealed that genetic changes in the primary tumors are generally retained in their matching metastasis (Perou et al, 2000;Weigelt et al, 2003).To decipher the mechanism for deregulated expression of TRAF4, we performed FISH analysis on TMA slides containing 125 TRAF4-positive and negative tumor samples from breast, ovary, lung, colon, pancreas and thyroid origins. As shown on Figure 1j and k, a maximum of 10 TRAF4 gene copies per tumor cell was seen.…”

“…This suggests that TRAF4 upregulation is more likely gained at an early stage of tumorigenesis rather than being acquired during cancer progression. Accordingly, gene expression profiles of primary breast carcinomas have revealed that genetic changes in the primary tumors are generally retained in their matching metastasis (Perou et al, 2000;Weigelt et al, 2003).…”