**6.3 E2F family**

The E2F family of transcription factors are direct targets of the hypo-phosphorylated Rb cell cycle regulation machinery, so many E2F members promote the transcription of pro-proliferative genes and controls the entry into S phase (reviewed in [65, 66]). AIB1 interacts with E2F family members through its N-terminal bHLH-PAS domain to promote the transcription of cdc25A, cdc6, MCMs, cyclins and Cdk. Depletion of AIB1 prevents cells from entering S-phase and undergoing mitosis. Furthermore, AIB1 controls its own expression through binding to E2F1 on its own promoter. As a result, AIB1 levels increase during G1 [9, 29]. Not only does E2F interact with AIB1 at its own promoter, but it also acts on other transcription factors, such as SP1, to further augment AIB1 expression [67]. This shows that direct and indirect binding of cell cycle effectors promote transcription of AIB1. Recently, the importance of an AIB1-E2F1 axis was highlighted while studying the efficacy of CDK4/6 inhibitor Palbociclib across all subtypes of breast cancer; AIB1 loss partially phenocopied Her2 inhibition and correlated with the CDK4/6 inhibitor treatment [68]. Thus, AIB1 contributes to cell cycle progression through E2F interaction, which is commonly dysregulated in cancer. This directly links AIB1 to regulation of cell cycle progression, implicating AIB1 further in pro-proliferative activities separate from external stimuli and nuclear receptor interaction.

**57**

*The AIB1/NCOA3/SRC-3 Oncogene*

**6.4 ETS factors**

**6.5 NF**κ**B pathway**

**6.6 STAT6**

in Section 3.2 [80].

**7. AIB1 as an oncogene**

regulation to control its potency.

*DOI: http://dx.doi.org/10.5772/intechopen.80925*

down of AIB1 abrogated most of their expression [71].

more complete list of proteins that interact with AIB1.

**7.1 Genetically engineered mouse models**

The Ets1, Ets2, and Pea3 members of the Ets family of transcription factors bind

to DNA in response to upstream Her2 activation and resulting kinase cascades, mediated by ERK and JNK [69]. The Ets family members have been shown to be coexpressed with AIB1 and both independently serve as a negative prognostic marker in breast and lung cancer [70, 71]. AIB1 was later shown to interact directly with the Ets family members to potentiate transcription of matrix metalloproteinases such as MMP2 to promote cell invasion and metastasis in vitro and in patients [71–73]. Once phosphorylated by ERK3 at S857, AIB1 specifically localized to the promoters of MMP2 and MMP9 in complex with Pea3 to promote invasive behavior [74]. Interestingly, these MMP targets seem highly dependent on AIB1 levels, as knock-

Though many binding partners are shared between members of the NCOA family, mostly between SRC-1 and AIB1, cooperation with IKK is unique to AIB1. IKK mediates the degradation of IkB, the inhibitor of NFκB, in response to TNFα stimulation. Interestingly, in parallel to this, AIB1 is phosphorylated by IKK,

increasing its nuclear localization and then can act on NFκB bound to DNA through its C-terminal activation domain [11, 75]. This emphasizes the ability of AIB1 to be to play a multi-faceted role within a signaling pathway, and the importance of its

Opposed to its role in the NFκB pathway, where AIB1 is the unique family member interacting with a kinase, STAT6 solely interacts with SRC-1. However, this does not mean AIB1 does not play a critical role. While SRC-1 directly interacts with STAT6 on the chromatin via its bHLH domain, AIB1 cannot. Recruited p300 bound to STAT6 can then recruit AIB1, which potentiates STAT6 signaling. This represents a unique cooperation between SRC-1 and AIB1, as SRC-1 is required for the co-activation of STAT6, and AIB1 then potentiates the transcription complex's activity. This was found to be an IL-4 dependent interaction, which acts in a dosedependent manner [76–79]. Such interactions are controlled by PP2A, as described

We attempted to highlight some of the most categorized interactions between AIB1 and transcription factors that are well studied oncogenes. See **Figure 1** for a

Genetic models have also clearly established AIB1 as an oncogene in multiple cancer types. Genetically engineered mouse models that overexpress AIB1 have been shown to increase incidence and growth of tumors, as well as significantly increase hyperplasia in the breast [7]. This is not solely due to its interaction with the estrogen receptor, the same mice presented an increase in tumors in hormone
