Lm. Varela et al., TNF alpha induces NF kappa B/p50 in association with the growth and morphogenesis of normal and transformed rat mammary epithelial cells, J CELL PHYS, 188(1), 2001, pp. 120-131
In contrast to the cytotoxic or cytostatic effect of TNF alpha on many brea
st cancer cell lines, TNF alpha stimulates growth and morphogenesis of norm
al rat mammary epithelial cells (MEC). The present studies were carried out
to determine whether there are intrinsic differences between normal and ma
lignant MEC which may explain the differing responsiveness to TNF alpha. Fr
eshly isolated rat MEC organoids from normal mammary gland or 1-methyl-1-ni
trosourea-induced mammary tumors were treated with TNF alpha for 21 days. U
nexpectedly, TNF alpha stimulated growth and morphogenesis of both normal a
nd transformed MEC in primary culture, although in transformed cells its ef
fects were delayed and the majority of the colonies were histologically abn
ormal, with multiple cell layers and no lumen. Since NF kappaB is a key med
iator of TNF alpha action and has been implicated in carcinogenesis, the ex
pression of the p50, p52, p65, and c-rel NF kappa -B proteins in normal and
transformed MEC was determined. Expression of p52 was significantly reduce
d in tumor cells, and p50 was absent, although its putative precursor, p105
was abundant. There were no changes in the levels of p65 or c-rel. TNF alp
ha induced a pronounced and sustained increase of a p50 homodimeric NF kapp
aB/DNA complex in both normal and transformed MEC. However, in transformed
MEC, NF kappaB binding was initially undetectable but then increased in res
ponse to TNF alpha. Thus, NF kappaB expression and DNA binding activity are
altered during mammary carcinogenesis. In addition, the significant increa
se in NF kappaB/p50 DNA-binding was temporally coincident with TNF alpha -i
nduced growth and morphogenesis, suggesting that it may play a significant
role in both normal development and carcinogenesis. (C) 2001 Wiley-Liss Inc
.