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.

Fig. 1.

(A) Unsupervised hierarchical clustering of 16 matching primary breast and metastatic tumors from eight patients, measured over 18,336 genes. The dendrogram has two large branches; the orange bar represents ER-α-negative tumors, the green bar represents ER-α-positive tumors. Alignment of six matching pairs was established, grouping of two pairs in one subbranch. META, metastasis; PRIM, primary tumor. (B) Two-dimensional representation of a multidimensional scaling analysis of eight matching primary and metastatic tumors using 18,336 genes. x and y axes; distance in arbitrary units. A thick red line indicates two-way-pairing, and a thin red line indicates one-way pairing. Np(n = 1-8), patient number primary tumor; nm(n = 1-8), patient number distant metastasis.

Fig. 2.

Permutation test of the within-pair-between-pair-scatter ratio (WPBPSR). Blue, null hypothesis distribution. Distribution after randomization of the labels of the primary and metastatic tumors, repeated 10,000 times (WPBPSR = 1 ± 0.05). The red line represents the WPBPSR of the eight matching primary and metastatic tumor pairs (WPBPSR = 0.67; P < 0.001).