**6.1 AP-1**

*Oncogenes and Carcinogenesis*

with loss of both ER and PR expression [45]. Moreover, AIB1 strongly binds AR and co-activates its target gene transcription. In prostate cancer, AIB1 is shown to be overexpressed and its levels correlate with higher tumor grade and increased disease recurrence but did not correlate with serum PSA levels [46]. Several studies have established AIB1 as a preferred coactivator for hormone-activated AR. Mutations in AR that alter its binding potency to AIB1 has been found in prostate cancer patients,

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 migra-

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

Though AIB1 has been primarily studied for its interaction with the Estrogen receptor (see Section 4), AIB1 interacts with a diverse set of transcription factors which may explain its oncogenic role in cancer. We will focus on the interaction of AIB1 with known oncogenic transcription factors to highlight the importance of AIB1 as a transcriptional co-activator across a variety of signaling pathways. As a general pattern, AIB1 acts to potentiate transcription of signaling pathways; when it binds to a transcription factor, it tends to increase the expression of target genes synergistically. Additionally, many pathways simultaneously activate their effectors and act on AIB1 in

suggesting an oncogenic role of AIB1 in prostate cancer [40].

tion and MDA-MB-231-induced breast tumor metastasis [25].

from AIB1-induced mammary tumors [51].

**6. AIB1 interacts with transcription factors**

**5. AIB1 potentiates membrane receptor signaling**

**54**

The activator protein transcription factor is a heteromeric complex consisting of Fos, Jun, ATF, and MAF family members, and can act as an oncogene that drives proliferative signaling. The complexes regulate a large swath of human gene expression and can contribute to both pro- and anti-tumorigenic gene expression (reviewed in [52]). AIB1 uses its C-terminal activation domains to interact with the Fos and Jun family members to activate and potentiate signaling, as measured by synthetic luciferase reporter assays and target gene expression [10]. Clinically, this interaction has been identified to be relevant in driving many pro-proliferative cancer genes. In hormone independent prostate cancer, responsiveness to IGF-Akt signaling by AIB1-AP-1 cooperation synergizes their effects on the transcription of target genes, thereby promoting cell growth and division [53]. In both hormonedependent and -independent breast cancer (in which AIB1 is amplified), AIB1 interaction with and co-activation of AP-1 specifically promotes the transcription of matrix metalloproteinases, contributing to invasive progression [54]. Such invasive behavior has also been linked to turnover of Focal Adhesions by AIB1 through an AP-1 dependent interaction [55]. Of note, the AIB1Δ4 isoform contains the domains necessary to interact with AP-1 and FAK, which may explain some of its endogenous role, as well as a dual functionality of this oncogenic isoform [25, 55].
