Carcinogenesis, Vol 18, 1069-1074, Copyright © 1997 by Oxford University Press
Y Wu, N Barnabas, IH Russo, X Yang and J Russo
Microsatellite instability (MSI) and loss of heterozygosity (LOH) in
chromosomes 9 and 16 have been reported in human breast cancers. In order
to determine whether changes in these chromosomes play a role in the
initiation and progression of this disease, we performed microsatellite
polymorphism analyses in human breast epithelial cells (HBEC) transformed
by chemical carcinogens, an in vitro system that recapitulates various
stages of neoplastic transformation. In this experimental system we studied
the mortal HBEC MCF-10M, immortal MCF- 10F cells, derived from MCF-10M
cells, and clones derived from MCF-10F cells treated with benzo[a]pyrene
(B[a]P) (BP1 and BP1E) and 7,12- dimethylbenz[a]anthracene (DMBA) (D3 and
D3-1). The four clones of transformed cells were injected into severe
combined immunodeficient (SCID) mice. Only BP1-E cells induced the
formation of tumors, designated BP1E-Tp cells. These cells originated six
additional tumors, designated BP1E-Tf no. 1 through Tf no. 6.
Microsatellite analyses were carried out using five markers for chromosome
9 and 20 for chromosome 16. There was no evidence of MSI or LOH in clones
BP1 and BP1E when compared with the MCF-10M and MCF-10F cells, whereas
BP1E-Tp cells and Bp1E-Tf no. 1-Tf no. 6 tumors exhibited MSI at loci p23
and p21, and LOH at p21-22 of chromosome 9. They also exhibited MSI and LOH
at multiple loci of both the short and long arms of chromosome 16, i.e.
p13.13, p13.3, p12, q12.1, q12.2, q23 and q24, to which putative tumor
suppressor genes have been localized. Clones D3 and D3-1 exhibited no
genomic changes in chromosome 9, but did show MSI at locus q12.1 of
chromosome 16 using marker D16S285. Although the cells treated with DMBA
expressed early phenotypes of neoplastic transformation, they were not
tumorigenic, and also manifested fewer changes than the tumorigenic BP1E-Tp
cells and the tumors BP1E-Tf. The changes in chromosomes 9 and 16 observed
in these latter ones indicated an association with the expression of
tumorigenesis, which represents a late event in the progression of the
neoplastic transformation of HBEC. Of interest was the observation that
HBEC transformed by chemical carcinogens in vitro express genomic changes
similar to those found in spontaneous breast carcinomas.
ARTICLES
Microsatellite instability and loss of heterozygosity in chromosomes 9 and 16 in human breast epithelial cells transformed by chemical carcinogens
Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
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