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

• Published in: Cancer research (Chicago, Ill.) Vol. 60; no. 5; pp. 1332 - 1340
• Main Authors: QIAO LIN, C, SINGH, J, MURATA, K, ITAHANA, Y, PARRINELLO, S, LIANG, S. H, GILLETT, C. E, CAMPISI, J, DESPREZ, P.-Y
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.2000
• Subjects: Animals; BASIC BIOLOGICAL SCIENCES; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Division - genetics; Cell Transformation, Neoplastic - genetics; Estrogens - metabolism; Estrogens - pharmacology; Female; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Helix-Loop-Helix Motifs; Humans; Inhibitor of Differentiation Protein 1; Mammary gland diseases; MAMMARY GLANDS; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Medical sciences; Mice; NEOPLASMS; Neoplasms, Hormone-Dependent - genetics; Neoplasms, Hormone-Dependent - pathology; PHENOTYPE; Repressor Proteins; STEROID HORMONES; Transcription Factors - biosynthesis; Transcription Factors - genetics; Tumor Cells, Cultured; Tumors; Human; Cell proliferation; Transcription promoter; Tumoral tissue; Estrogen; Malignancy; Malignant tumor; Gene expression; In vitro; Mammary gland diseases; Phenotype; Established cell line; Metastatic; Mammary gland; Progesterone; Transcription factor; Sex steroid hormone; Tumor cell
• ISSN: 0008-5472; 1538-7445

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 al., Mol. Cell. Biol., 18: 4577-4588, 1998) that ectopic expression of Id-1 inhibits differentiation and stimulates the proliferation and invasiveness of mouse mammary epithelial cells, and that there is a correlation between the levels of Id-1 protein and the aggressiveness of several human breast cancer cell lines. Here, we show that aggressive and metastatic breast cancer cells express high levels of Id-1 mRNA because of a loss of serum-dependent regulation that is mediated by a 2.2-kb region of the human Id-1 promoter. Three lines of evidence suggest that unregulated Id-1 expression may be an important regulator of the aggressive phenotype of a subset of human breast cancer 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 important mediator of the effects of sex steroid hormones on T47D cell proliferation. Estrogen stimulated proliferation and induced Id-1 expression, whereas progesterone inhibited proliferation and repressed Id-1 expression. Progesterone repressed Id-1 expression, at least in part by repressing transcription. Most importantly, an antisense oligonucleotide that reduced Id-1 protein levels reduced the ability of estrogen to stimulate cell proliferation, whereas constitutive Id-1 expression rendered cells refractory to growth inhibition by progesterone; and (c) using a limited number of breast cancer biopsies, we showed that Id-1 was more frequently expressed in infiltrating carcinomas compared with ductal carcinomas in situ. Our results suggest that Id-1 can control the malignant progression of breast cancer cells, particularly that mediated by sex steroid hormones. Moreover, Id-1 has the potential to serve as a marker for aggressive breast tumors.