**7.3 AIB1 promotes metastasis**

As AIB1 acts to potentiate a variety of signaling cascades, it contributes not only to the growth of the primary cancerous lesion, but also promotes metastasis to distant sites. AIB1 loss suppressed lung metastasis in MMTV-PyMT breast cancer models, significantly reducing the ability of the cells to metastasis. Following transplantation of the AIB1−/− tumors from knockout mice to wild-type PyMT mice, metastasis was completely lost [74]. Pancreatic and breast tumors formed in AIB1−/− also exhibit a more epithelial, E-cad high tumor phenotype, suggesting

a repression of epithelial-mesenchymal transition [74]. This is reflected in patient data, where more PDAC patients samples with lymph node metastasis (68%) stain positive for nuclear AIB1, as opposed to patients without metastasis, who also stain negative for AIB1 (42%) [95]. Similarly, in papillary thyroid cancer, levels of AIB1 positive increase significantly from high grade lymph node positive disease (73.2%), compared to non-metastatic disease (41.2%) [96]. Patient samples highlight the role of AIB1 in metastasis, as presence of nuclear staining not only correlates with increased disease grade, but metastasis rate.

In molecular studies, specific transcription factor interactions with AIB1 have been identified as integral to promoting metastasis. The ERK3 mediated interaction of AIB1 with the Ets family member PEA3 results in the oncogenic transcription of matrix metalloproteinases MMP2 and MMP9, which promote an EMT phenotype and destruction of the surrounding extracellular matrix, leading to invasion [74]. Reduction of ERK3 or AIB1 by shRNA attenuates metastasis in lung cancer models; unsurprisingly ERK3 is also upregulated in lung cancer clinical samples [71]. Similarly, AIB1 interaction with AP-1 upregulates MMP7 and MMP10, leading to increased metastasis in breast cancer, regardless of hormone receptor status. Alternatively, AIB1 binds to the promoters of Notch intracellular domain targets to enhance Notch proliferative signaling and effecting cell cycle progression in colorectal cancer. AIB1 reduction by genetic knockout reduced the Notch targets HES1 as well as Cyclins (likely controlled by E2F1-AIB1, however). Reduction of AIB1 levels yields significantly reduced tumor burden and lung metastasis [94].

Finally, an underexplored area of AIB1 activity may be its role in promoting invasion and migration by facilitating oncogenic transcription factor cooperation. Recently, AIB1 was shown to be recruited to larger TEAD and AP-1 transcription factor complexes, and promote cooperative transcription of DOCK4 and DOCK9, thereby increasing mobility [59]. Endogenous TEAD and AP-1 share a significant degree of genomic co-enriched ChIP-seq peaks, and it remains to be seen exactly how much of this is mediated by AIB1, as the two transcription factors are potent oncogenes [62]. Further, transcription factor cooperation has been suggested with TEAD, AP-1, SRF, and other stimuli responsive transcription factors—determining to what extent AIB1 or other NCOA family members are relevant to such signaling networks is an unanswered question [60, 63, 64].
