Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells.

Abstract

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.

• Authors: Yoko Itahana, Jarnail Singh, Tomoki Sumida, Jean-Philippe Coppe, Simona Parrinello, James L Bennington, Pierre-Yves Desprez
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 21 Pg. 7098-105 (Nov 01 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14612502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA-Binding Proteins
• ID2 protein, human
• Idb2 protein, mouse
• Inhibitor of Differentiation Protein 2
• Laminin
• Repressor Proteins
• Transcription Factors

Topics

• Animals
• Biopsy
• Breast Neoplasms (metabolism, pathology)
• Cell Differentiation (physiology)
• Cell Line, Tumor
• DNA-Binding Proteins (biosynthesis, genetics, physiology)
• Disease Progression
• Gene Expression Regulation
• Humans
• Inhibitor of Differentiation Protein 2
• Laminin (physiology)
• Mammary Glands, Animal (cytology, metabolism)
• Mice
• Prognosis
• Repressor Proteins
• Transcription Factors (biosynthesis, genetics, physiology)