The extent of chromosomal rearrangements correlates positively with the level of expression of the nuclear matrix high mobility group (HMG) proteins HMGI(Y) when tested in three human prostate cancer cell lines (PC-3 > DU-145 > LNCaP). HMGI(Y), topoisomerase II, and A-T-rich sequences have been reported to be located at the base of the DNA loop domains in both the nucleus and chromosome and are juxtapositioned for chromosomal rearrangement. Transfecting and expressing full-length HMG-I into the LNCaP cell markedly enhanced the presence and heterogeneity of unbalanced (nonreciprocal) chromosomal rearrangements but not of balanced rearrangements. Unbalanced chromosomal rearrangements are common in solid human tumors.