AIB1 (amplified in breast cancer 1) is the only member of the SRC (steroid receptor coactivator) family amplified and overexpressed in many epithelial tumors. AIB1 is rate-limiting for estrogen (E) dependent tumor development but emerging data ascribes an E-independent role for AIB1 whereby AIB1 is rate-limiting for IGF-1, EGF and heregulin-induced transcription & phenotypic changes important for tumor progression. The mechanism(s) of AIB1's potentiation of growth factor signaling is completely unknown. We now report that a rapid increase in tyrosine phosphorylation of AIB1 occurs within minutes of growth factor treatment, paralleled by nuclear translocation and rapid association of AIB1 with cytoplasmic signaling molecule(s), e.g. IRS-1. We hypothesize that tyrosine phosphorylation of AIB1 promotes interactions with critical signaling molecules that initiate nuclear translocation and transcriptional coactivator activity.
Specific Aims :
Aim 1 : To determine the mechanisms and the function of tyrosine phosphorylation of AIB1 due to IGF-1, EGF and Heregulin stimulation of cells. A) We will identify the tyrosine residues phosphorylated in AIB1 after IGF, EGF or Heregulin treatment. B) We will determine the role of these tyrosine residues in AIB1 for: (i) translocation of AIB1 to the nucleus and (ii) transcriptional activity of AIB1. C) We will determine the upstream pathways leading to tyrosine phosphorylation of AIB1 due to IGF-1, EGF and Heregulin stimulation.
Aim 2 : To determine the role of AIB1 in growth factor mediated mammary tumorigenesis. A) We will determine whether gain or loss of AIB1 or AIB1-?3 alters preneoplasia, onset, incidence, metastatic spread and gene expression pattern of mammary adenocarcinoma in MMTV/neuT mice. B) We will determine if AIB1 directly affects IGF-1, EGF or Heregulin pathways by examining signaling in mammary organ culture derived from MMTV/neuT mice with gain or loss of AIB1 or AIB1-??
Showing the most recent 10 out of 14 publications
