**6.4 ETS factors**

*Oncogenes and Carcinogenesis*

family [61].

and unanswered question.

and nuclear receptor interaction.

**6.3 E2F family**

transformation of normal tissue and the progression of disease. The effectors bind with the TEAD family of proteins to exert their oncogenic potential as a transcription factor complex [56–58]. Before paralogs YAP and TAZ, were implicated as transactivators of the TEAD family of transcription factors, the TEAD family was shown to interact with all the members of Nuclear Coactivator Family [8]. Specifically, the bHLH-PAS domain of AIB1 interacts with TEADs, likely in a larger complex with YAP or TAZ, and may then recruit histone modifying proteins to propagate transcription as measured by target genes [59]. Similarly, knockdown of AIB1 in cell lines significantly reduces TEAD target genes CTGF and CYR61 [60]. Currently, it is unclear to what extent the oncogenic YAP/TAZ-TEAD complex requires AIB1 or other members of the NCOA family to act as oncogenes. Knockdown of AIB1 in multiple studies has resulted in a modest, but significant reduction of TEAD transcriptional targets [60]. Interestingly, the Drosophila homolog of AIB1, called Taiman, contains PPxY motifs that are known to interact with the YAP homolog at its conserved WW domain. These PPxY motifs, however, are neither conserved in human AIB1, nor any member of the NCOA/SRC/p160

Importantly, AIB1 may be the critical mediator of TEAD cooperation with AP-1. Early reports show an oncogenic signature associated with AP-1 and TEAD co-occupancy in triple negative breast cancer that promotes more aggressive disease [62]; this interaction was recently show to be mediated by AIB1 acting as a bridge between AP-1 and TEAD [59]. However, a clear panel of genes co-regulated by AIB1-TEAD interaction has yet to be elucidated. Further, while reports have shown AIB1 to be part of the TEAD-SRF (Serum Response Factor) complex, the data is unclear as to whether AIB1 is required for complex formation, or whether YAP can recruit SRF in the absence of AIB1 [60, 63]. It is apparent that TEAD, AP-1, and SRF all have coordinated responses to external growth stimuli [64], but the extent to which AIB1 and other co-activators are required to propagate and potentiate oncogenic signaling remains an exciting

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

**56**

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