**7.4 The role of AIB1Δ4 in metastasis**

The AIB1Δ4 isoform is an N-terminally truncated splice variant that lacks the bHLH-PAS domain. In vitro it localizes significantly less in the nucleus, and shuttles more often between the nucleus and cytoplasm. It may be more readily retained in the cytoplasm because of its interaction with FAK and its role in focal adhesions (see Section 2.2) [25]. Interestingly we have found that metastatic MDA-MB-231 triple negative cell lines and metastatic Colo357 pancreatic ductal adenocarcinoma lines have significantly higher AIB1Δ4/AIB1 ratio than their parental counterparts [22]. This aggressive phenotype may be due to loss of transcriptional repression by ANCO1, as we have shown previously [24].

In the cell periphery, AIB1Δ4 interacts with FAK in lamellipodia and filopodia in response to EGF stimulation in breast cancer cells. The isoform in unable to bind to the promoters of the MMPs previously described. Instead, it is phosphorylated by PAK1 which facilitates interaction with EGFR and FAK to promote transwell migration in vitro. These findings correlated with in vivo studies showing overexpression AIB1Δ4 significantly increased metastasis to the lymph node and lung [25]. These data match our earlier findings in isotypic cell lines and highlight the many ways this understudied isoform may be contributing to normal and disease biology.

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cell stress [105].

**Conflict of interest**

*The AIB1/NCOA3/SRC-3 Oncogene*

**7.5 Therapeutics and AIB1**

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

nism of taxol resistance in breast cancer [31].

**8. Discussion and conclusion**

Briefly, AIB1 can contribute to chemo- or hormonal therapeutic resistance, promoting disease relapse. Early indications of this 'escape route' came about when stratifying AIB1 levels and outcomes of ER+ patients treated with tamoxifen, a selective estrogen receptor modulator that is a first line treatment. Patients with high AIB1 levels after receiving treatment had significantly worse outcomes than those with low AIB1 (oddly, patients who never received tamoxifen and also had AIB1 did significantly better; this has yet to be explained). The same study showed conclusively that high levels of Her2/Neu and AIB1 significantly increase the chance of relapse, likely due to crosstalk between growth factor and hormone signaling pathways that thereby circumvent estrogen dependence [42, 97, 98]. Later, it was shown that direct competition between AIB1 and PAX2 occurs on the ERBB2 gene body encoding Her2. Loss of PAX2 reverses repression of Her2 transcription mediated by tamoxifen, and ectopic expression reverts AIB1 mediated tamoxifen resistance [99]. Finally, upregulation of AIB1 has also been shown to be a mecha-

AIB1 in an oncogene that contributes to disease progression in multiple cancers.

Most clinical studies have underscored the importance of AIB1 in the progression of human disease. Overwhelmingly, expression of AIB1 is correlated with poor prognosis in breast, ovarian, pancreatic, prostate, and colon cancer, as well as increased metastasis [25, 100]. Heightened AIB1 levels have successfully been used in the clinic as a negative prognostic marker in post-menopausal breast cancer [101] and may mark tamoxifen resistance [102]. Further, preclinical investigation of compounds that promote the degradation of AIB1 have shown promising results in attenuating the effects of the oncogene [103, 104]. Interestingly, pharmacological hyperstimulation of AIB1 has also been shown to induce cell death by increasing

Clarifying the extent to which AIB1 is critical in bridging cooperating transcription factors will further explain intracellular signaling biology and may also provide new targets for therapeutic development. Also, there remains a gap in knowledge surrounding the role of the AIB1Δ4 in the nucleus, especially in regard to global binding and transcriptional patterns of the isoform. Finally, elucidating the importance of AIB1 as an effector of growth factor and cytokine signaling may explain its potent oncogenic nature. It is clear that AIB1 may be both a clinically relevant prognostic marker and a

promising therapeutic target, as evidenced by the promising preclinical data.

The authors declare no conflicts of interest.

It primarily acts to augment transcriptional activity, thereby amplifying proproliferative and pro-tumorigenic signaling cascades through binding to its many partners. Though primarily studied for its role in interacting with nuclear hormone receptors, AIB1 has been clearly implicated to play an oncogenic role in hormone independent cancers. Genetic manipulation or removal of the NCOA3 gene has almost universally slowed cancer progression wherever studied, likely by dampening all of the pathways it usually effects. From this role, its clinical importance is

obvious, as its elevated levels is usually a negative prognostic marker.
