A role for Id proteins in mammary gland physiology and tumorigenesis.

Id helix-loop-helix (HLH) proteins are regulators of cell growth and differentiation in embryonic and adult tissues. They are members of the basic HLH family of transcription factors but lack a DNA binding domain. By binding to basic HLH transcription factors, Id proteins regulate gene expression. Id1 and Id3 have extensive sequence homology and similar patterns of expression during embryogenesis and in adult tissues. They are also expressed at high levels in the endothelial cells of tumor-infiltrating blood vessels, and breast tumors spontaneously arising in MMTV-neu mice demonstrate impaired angiogenesis when growing in an Id1- and/or Id3-deficient background. These lesions are typically cystic with a small rim of viable tumor cells surrounding an acellular necrotic core. Id2 plays a critical role in breast differentiation and lactation. Id4 regulates BRCA1 expression and may be involved in hormone-dependent regulation of BRCA1 homeostasis. Thus, all four members of the Id protein family play pivotal roles in distinct aspects of normal and malignant breast biology, the subject of this review.