Insulin receptor substrate-1 regulates the transformed phenotype of BT-20 human mammary cancer cells.
Although originating from a human breast cancer, BT-20 cells do not form colonies in soft agar. BT-20 cells do not express insulin receptor substrate-1 (IRS-1), which is known to promote both normal and abnormal growth and to inhibit differentiation. Stable expression of IRS-1 confers to BT-20 cells the ability to form colonies in soft agar. BT-20 cells form tumors in xenografts in mice, but the size of tumors is twice as large when the cells express IRS-1. The increased transformed phenotype is characterized by occupancy of the rDNA and cyclin D1 promoters by IRS-1 and the activation of the cyclin D1, c-myc, and rDNA promoters. In addition, the retinoblastoma protein, which is detectable in the rDNA promoter of quiescent BT-20/IRS-1 cells, is replaced by IRS-1 after insulin-like growth factor-I stimulation. Our results indicate that in BT-20 human mammary cancer cells, expression of IRS-1 activates promoters involved in cell growth and cell proliferation, resulting in a more transformed phenotype. Targeting of IRS-1 could be effective in inhibiting the proliferation of mammary cancer cells.
Dalmizrak
Ozlem
O
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
Wu
An
A
Chen
Jia
J
Sun
Hongzhi
H
Utama
Fransiscus E
FE
Zambelli
Diana
D
Tran
Thai H
TH
Rui
Hallgeir
H
Baserga
Renato
R
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D047369:Chromatin Immunoprecipitation; D005260:Female; D019940:Genes, bcl-1; D016259:Genes, myc / Q000502:physiology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010641:Phenotype; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D016160:Retinoblastoma Protein / Q000235:genetics
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D016160:Retinoblastoma Protein