Id
proteins are inhibitors of
basic helix-loop-helix transcription factors and generally stimulate cell proliferation and inhibit differentiation. We have shown that ectopic expression of Id-1 in murine mammary epithelial cells resulted in loss of differentiation and gain of invasive and proliferative abilities. Moreover, Id-1 was highly expressed in aggressive
breast cancer cells in culture and in biopsies from infiltrating
carcinomas. In contrast to Id-1, we found that, in vitro and in vivo,
Id-2 mRNA and
protein were up-regulated as mammary epithelial cells lost proliferative capacity and initiated differentiation. We further determined that this up-regulation of
Id-2 was a necessary step toward a fully differentiated phenotype in breast cells. Here we show that one of the components of the extracellular matrix network,
laminin, is responsible for the increase in
Id-2 expression during differentiation. We also show that
Id-2 expression is inversely correlated with the rate of proliferation in murine mammary epithelial cells and that
Id-2 is expressed at a higher level in differentiated human
breast cancer cells in comparison with very aggressive and metastatic cells. When reintroduced in aggressive
breast cancer cells,
Id-2 is able to reduce their proliferative and invasive phenotypes and decrease their level of
matrix metalloproteinase 9 secretion as well as increase
syndecan-1 expression. Moreover, little
Id-2 protein expression is detectable in human biopsies from aggressive and invasive
carcinomas in comparison with in situ
carcinomas. In conclusion,
Id-2 expression not only follows a pattern opposite to that of Id-1 during mammary gland development and
breast cancer progression but also appears to act as an important
protein for the maintenance of a differentiated and noninvasive phenotype in normal and transformed breast cells.