Insulin receptor substrate 1 modulates the transcriptional activity and the stability of androgen receptor in breast cancer cells.
Breast cancer development and progression is regulated by growth factors and steroid hormones. Although the majority of human breast cancers expresses androgen receptor (AR), the role of androgens in breast tumorigenesis remains largely unexplored. Here we demonstrate that an AR ligand, 5-alpha-dihydrotestosterone (DHT), inhibits MCF-7 breast cancer cell growth induced by insulin like growth factor 1 (IGF-I). Our results show that DHT induces association of AR with IRS-1, the major IGF-1 receptor signaling molecule. The AR/IRS-1 complex translocates to the nucleus and is recruited to gene promoters containing androgen responsive elements causing an increase of AR transcriptional activity. Moreover, IRS-1 knockdown suggests that IRS-1/AR interaction decreases the ubiquitin/proteasome dependent degradation of AR, increasing its stability. Taken together, these data indicate that nuclear IRS-1 is a novel AR regulator required to sustain AR activity and demonstrate, for the first time in breast cancer cells, the existence of a functional interplay between the IGF system and AR. This interplay may represent the molecular basis of mechanisms through which androgens exert their inhibitory role on the proliferation of breast cancer cells.
Department Farmaco-Biologico, University of Calabria, Arcavacata di Rende (CS) 87036, Italy.
Marilena
M
Lanzino
Cecilia
C
Garofalo
Catia
C
Morelli
Maria
M
Le Pera
Ivan
I
Casaburi
Michael J
MJ
McPhaul
Eva
E
Surmacz
Sebastiano
S
Andò
Diego
D
Sisci
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D013196:Dihydrotestosterone / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D011944:Receptors, Androgen; D013196:Dihydrotestosterone