**7.2 AIB1 levels and clinical outcome**

Patient data has shown that the levels of AIB1 correlate with the severity and stage of disease. In each tissue type of origin, it is likely that AIB1 is acting as an oncogene in a different capacity or selectively amplifying a variety of oncogenic signals. We have described a few specific cancer types below that detail the predictive capacity of AIB1 in disease progression.

	- Early stage breast cancer: only 20–30% of women with stage 0 Ductal Carcinoma In Situ (DCIS) will progress to invasive disease. It is still unclear what factors promote the invasion, as genetic expression signatures of DCIS patients resemble those of invasive disease [85, 86]. We have shown that AIB1 is required for the formation of DCIS lesions in mice, and loss of AIB1 increases tumor necrosis, and decreases proliferation and tumor burden. Further, genetic ablation of AIB1 significantly reduces CD44+/CD24– breast cancer initiating cells, thus more closely resembling differentiated luminal epithelium. This is in part due to disruption and downregulation of the Notch and Her2 signaling pathways, where AIB1 was shown to regulate mRNA expression of Notch, Jag, and DLL family members [87]. Thus, AIB1 may be promoting a breast cancer initiating cell subpopulation that is required to promote the invasive transition.

**59**

*The AIB1/NCOA3/SRC-3 Oncogene*

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

stained positive for nuclear AIB1, whereas less than 10% of patients with cystomas or borderline cancer cases stained positive. [26] AIB1 polymorphs at the sequence level may also be predictive of ovarian cancer. CAG sequence polymorphisms within the glutamate track (poly-Q region) of AIB1 may also be predictive of ovarian cancer aggressiveness—codon lengths can vary between 24 and 30 repeats. The shorter the track, the shorter the time to disease recur-

• Pancreatic cancer: AIB1 is rarely expressed in normal pancreas ducts (<6% of patients) yet is increased in pancreatitis and high-grade neoplasia between 15 and 20% of samples. Finally, upon progressing to pancreatic ductal adenocarcinoma (PDAC), nearly 65% of patients are positive for AIB1 mRNA and protein. Some patients also present with increased copy number, which may explain some, but not all of the overexpression of AIB1. Of note, the AIB1Δ4 isoform is present in pancreatic cancer cell lines, suggesting it acts not only through dysregulated hormone receptor signaling, but may also be playing unexplored roles [89]. AIB1 has also been shown to increase inflammatory conditions by upregulating CXCL1, CXCL2, and CXCL5 during disease development in a mouse model [90]. This may partially explain why the increase of mRNA and protein in pancreatitis

and early stage disease is selected for as PDAC progresses in patients.

higher incidence and risk of the disease.

**7.3 AIB1 promotes metastasis**

• Prostate cancer: levels of AIB1 are associated with severity/grade of prostate cancer. Higher levels across all stages are a negative prognostic marker in recurrence free survival. The Kaplan Meyer curves are similar for PSA and nuclear AIB1, suggesting it could serve as a biomarker for disease prognosis and progression [46, 81]. Of note, the same polymorphic CAG sequence that may be prognostically relevant to ovarian cancer may be relevant to prostate cancer—a case study of Chinese men suggested an optimal length of mid-quantity CAG repeats [91]. However, these data need to be repeated in a population with a

• Colorectal cancer: overexpression of AIB1 was detected in 35% of samples, and amplification of the NCOA3 gene was detected in 10% of patients with colorectal cancer [92]. Levels not only varied significantly when compared to normal tissue, but also significantly increased by tumor grade [82]. One potential role of AIB1 in colorectal cancer is interaction with Estrogen Receptor Beta, which is expressed in CRC. In 110 patients, increasing grade of lesion showed significant upregulation in the levels of expression of AIB1, ERb, and SRC-2. Paradoxically, the same study noted both an increase in invasion associated with higher AIB1 levels, but an increase in survival outcome [93]. AIB1−/− mice were also unsusceptible to colorectal cancer induction by azoxymethane/dextran sodium sulfate treatment [94]. Clearly, more data is needed to explain the role of AIB1 in colorectal cancer,

and whether AIB1 may modulate pro- and anti-tumorigenic behavior.

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

As AIB1 acts to potentiate a variety of signaling cascades, it contributes not only

rence compared to patients with longer sequences [88].

*Oncogenes and Carcinogenesis*

affecting many pro-proliferative pathways.

AIB1 is acting as an oncogene.

**7.2 AIB1 levels and clinical outcome**

tive capacity of AIB1 in disease progression.

independent tissues, such as lung, skin, and bone, suggesting the oncogenic role of AIB1 may be mediated by a variety of different tissue specific transcription factor interactions [46, 81]. Removal of the NCOA3 gene that encodes AIB1 in v-Ha-Ras driven mouse model of breast cancer also delayed tumor formation by negatively impacting growth factor signaling [50]. In breast cancer studies, it is clear that AIB1 exerts its oncogenic potential through hormone receptor signaling and by positively

There have also been genetic models implicating AIB1 as a critical mediator of the development and maintenance of hormone responsive and castration resistant prostate cancer. In hormone sensitive prostate cancer, AIB1 mediates its effects through androgen receptor activity, eventual castration resistant/hormone insensitive disease was marked by AIB1 potentiation of Akt-mTOR signaling (similar to studies in the breast) [81–83]. Taken together, these data suggest that AIB1 is critical for the formation and progression of many cancer types, in both hormone dependent and independent settings. Especially in the hormone-independent diseases, it is critical to study the binding partners of AIB1 in order to better understand how

Patient data has shown that the levels of AIB1 correlate with the severity and stage of disease. In each tissue type of origin, it is likely that AIB1 is acting as an oncogene in a different capacity or selectively amplifying a variety of oncogenic signals. We have described a few specific cancer types below that detail the predic-

• Breast cancer: our group and others have shown that AIB1 is overexpressed and amplified in breast cancer compared to normal breast tissue [1, 20]. It is estimated that the mRNA expression in tumors is up between 10 and 60% in primary tumors, and increased 30% in metastatic sites [21, 84]. When stratified by grade of lesion, there is a clear positive correlation of AIB1 mRNA levels with worsening stage, with nearly a 65% increase in expression compared to normal tissue in grade 3 tumors [45]. We have also shown that increasing mRNA levels are associated with worse patient outcome [43]. These patients have dysregulated signaling pathways as previously described: augmented estrogen receptor signaling (in ER+ disease) and increased IGF/growth factor

○ Early stage breast cancer: only 20–30% of women with stage 0 Ductal

• Ovarian cancer: AIB1 was also found to be overexpressed and amplified in ovarian cancer [1]. In high grade ovarian cancer samples, 64% of patients

Carcinoma In Situ (DCIS) will progress to invasive disease. It is still unclear what factors promote the invasion, as genetic expression signatures of DCIS patients resemble those of invasive disease [85, 86]. We have shown that AIB1 is required for the formation of DCIS lesions in mice, and loss of AIB1 increases tumor necrosis, and decreases proliferation and tumor burden. Further, genetic ablation of AIB1 significantly reduces CD44+/CD24– breast cancer initiating cells, thus more closely resembling differentiated luminal epithelium. This is in part due to disruption and downregulation of the Notch and Her2 signaling pathways, where AIB1 was shown to regulate mRNA expression of Notch, Jag, and DLL family members [87]. Thus, AIB1 may be promoting a breast cancer initiating cell subpopulation that is

levels and enhanced in PI3K-Akt-mTOR pathway activity.

required to promote the invasive transition.

**58**

stained positive for nuclear AIB1, whereas less than 10% of patients with cystomas or borderline cancer cases stained positive. [26] AIB1 polymorphs at the sequence level may also be predictive of ovarian cancer. CAG sequence polymorphisms within the glutamate track (poly-Q region) of AIB1 may also be predictive of ovarian cancer aggressiveness—codon lengths can vary between 24 and 30 repeats. The shorter the track, the shorter the time to disease recurrence compared to patients with longer sequences [88].

