Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells.
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.
Itahana
Yoko
Y
Cancer Research Institute, California Pacific Medical Center, Stern Building, 2230 Clay Street, San Francisco, CA 94115, USA.
Singh
Jarnail
J
Sumida
Tomoki
T
Coppe
Jean-Philippe
JP
Parrinello
Simona
S
Bennington
James L
JL
Desprez
Pierre-Yves
PY
D000818:Animals; D001706:Biopsy; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2; D007797:Laminin / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D011379:Prognosis; D012097:Repressor Proteins; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; C497450:ID2 protein, human; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D007797:Laminin; D012097:Repressor Proteins; D014157:Transcription Factors