**5. AIB1 potentiates membrane receptor signaling**

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK). It is activated by EGF which mediates several functions including cell proliferation, cell survival, and development. AIB1 knockdown abrogated EGF growth response in lung, breast, and pancreatic cancer cell lines. This was a result of reduced tyrosine phosphorylation of EGFR at multiple residues both at autophosphorylation and Src kinase phosphorylation sites via less recruitment of Src homology 2 domaincontaining proteins to the EGFR. EGF-dependent phosphorylation of HER2 was also decreased yet no effect was seen on phosphorylation of platelet-derived growth factor receptor (PDGFR), HER3 or other RTKs. This suggests that the oncogenic effect of AIB1 may be mediated by EGFR and HER2 signaling pathways [47]. In a MMTV-Neu mouse model, homozygous deletion of AIB1 completely inhibits Neu-induced mammary tumor formation. The role of AIB1 in HER2/Neu oncogenic activity was elucidated in the Neu/AIB1+/− tumors showing decreased phosphorylated Neu, cyclin D1, and cyclin E [48]. In addition to its role as a transcription coactivator, AIB1 isoform, AIB1Δ4, can act in the periphery of the cell mediating EGFR and FAK direct interaction. Overexpression of AIB1Δ4 increased cell migration and MDA-MB-231-induced breast tumor metastasis [25].

The insulin-like growth factor (IGF)-I regulates protein turnover and has a role in cell proliferation and differentiation. IGF-I binds to its receptor activating a cascade of intracellular tyrosine kinases which phosphorylate downstream substrates including IRS and Shc [49]. AIB1 is rate-limiting for IGF-I signaling and functions in human breast cancer cells. Knockdown of AIB1 in MCF7 cells reduced IGF-1 stimulated anchorage-independent proliferation and IGF-I-dependent anti-anoikis [37]. In AIB1−/− mice, impaired insulin-like growth factor I pathway reduced mammary tumorigenesis and metastasis with no change in ER or PR regulated genes [50]. In addition, AIB1 regulates the expression of proteins involved in the IGF-1 signaling pathway. For example, inhibition of mTOR prevented mammary hyperplasia and hypertrophy that was caused by AIB1 overexpression in the mouse mammary gland. In mice, mTOR inhibition prevented the growth of xenografts from AIB1-induced mammary tumors [51].
