A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer cells

The helix-loop-helix protein Id-1 inhibits the activity of basic helix-loop -helix transcription factors, and is an important regulator of cell growth and tissue-specific differentiation. We have shown (P, Y, Desprez et at, Me l. Cell. Biol,, 18: 4577-4588, 1998) that ectopic expression of Id-1 inhibi ts differentiation and stimulates the proliferation and invasiveness of mou se mammary epithelial cells, and that there is a correlation between the le vels of Id-1 protein and the aggressiveness of several human breast cancer cell lines. Here, we show that aggressive and metastatic breast cancer cell s express high levels of Id-1 mRNA because of a loss of serum-dependent reg ulation that is mediated by a 2.2-kb region of the human Id-1 promoter. Thr ee lines of evidence suggest that unregulated Id-1 expression may be an imp ortant regulator of the aggressive phenotype of a subset of human breast ca ncer cells: (a) a constitutively expressed Id-1 cDNA, when introduced into a nonaggressive breast cancer cell line (T47D), conferred a more aggressive phenotype, as measured by growth and invasiveness; (b) Id-1 was an importa nt mediator of the effects of sex steroid hormones on T47D cell proliferati on. Estrogen stimulated proliferation and induced Id-1 expression, whereas progesterone inhibited proliferation and repressed Id-1 expression. Progest erone repressed Id-1 expression, at least in part by repressing transcripti on. Most importantly, an antisense oligonucleotide that reduced Id-1 protei n levels reduced the ability of estrogen to stimulate cell proliferation, w hereas constitutive Id-1 expression rendered cells refractory to growth inh ibition by progesterone; and (c) using a limited number of breast cancer bi opsies, we showed that Id-1, was more frequently expressed in infiltrating carcinomas compared with ductal carcinomas in situ, Our results suggest tha t Id-1 can control the malignant progression of breast cancer cells, partic ularly that mediated by sex steroid hormones. Moreover, Id-1 has the potent ial to serve as a marker for aggressive breast tumors.