The helix-loop-helix protein Id1 requires cyclin D1 to promote the proliferation of mammary epithelial cell acini.
Overexpression of the helix-loop-helix (HLH) protein Id1 has been associated with metastasis in breast cancer, but its role in models of early breast tumorigenesis is not well characterized. We show that the down-regulation of endogenous Id1 via proteosomal degradation and relocalization from the nucleus to the cytoplasm is an early event in the formation of mammary epithelial acini. Overexpression of Id1 in both human MCF-10A and primary mouse mammary epithelial cells disrupted normal acinar development by increasing acinar volume. This occurred in an HLH domain-dependent fashion via an increase in S phase. Id1 overexpression also increased apoptosis leading to accelerated luminal clearance, and this was reversed by coexpression of the proto-oncogene Bcl2, leading to large, disorganized structures with filled lumina. Id1 overexpression was unable to increase the volume of cyclin D1(-/-) acini, indicating that Id1 is dependent on cyclin D1 for its proliferative effects. In summary, Id1 may contribute to early breast cancer by promoting excessive proliferation through cyclin D1.
Caldon
C Elizabeth
CE
Cancer Research Program, Garvan Institute of Medical Research, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
Swarbrick
Alexander
A
Lee
Christine S L
CS
Sutherland
Robert L
RL
Musgrove
Elizabeth A
EA
D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division; D019938:Cyclin D1 / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D018257:Helix-Loop-Helix Motifs / Q000502:physiology*; D006801:Humans; D007223:Infant; D051798:Inhibitor of Differentiation Protein 1 / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D000090063:Proto-Oncogene Mas
C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019938:Cyclin D1