Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was originally discovered as the tumor suppressor gene frequently lost on chromosome 10q23 . PTEN is a phosphatase having both protein and lipid phosphatase activities. It is well-defined as a tumour suppressor that plays a critical role in cell survival and cell death . A high frequency of mutation in PTEN is associated with the development of various types of human diseases , including glioblastomas , prostate cancers , and endometrial carcinomas stimulated by tamoxifen [6, 7]. The complete loss of PTEN is also a common event in breast cancers that are caused by breast cancer 1 (BRCA1) deficiency . PTEN has a phosphatase (PPase) domain, which specifically dephosphorylates phosphoinositide-3,4,5-triphos-phate (PIP3), a potent activator of AKT. It therefore acts as a negative regulator of the PI3K/AKT signaling pathway, which is specifically involved in cell growth, apoptosis, transcription and cell migration. In addition to its phosphatase domain, PTEN also has a putative C2 regulatory (C2) domain and a C-terminal tail (Tail) containing two PEST homology regions that also play important roles in regulating its function [9, 10]. For example, PTEN can associate with the centromere by docking onto centromere protein C (CENP-C), a centromeric binding protein, resulting in the maintenance of chromosomal stability . A recent study has shown that PTEN can interact with anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase, and promote its association with cadherin 1 (CDH1), thereby enhances the tumor-suppression activity of the APC-CDH1 complex . In both cases, the phosphatase activity of PTEN is not required.
Amplified in breast cancer 1 (AIB1), also known as SRC-3/ACTR/RAC3/Ncoa3, is a member of the p160 family, which also includes SRC-1 and SRC-2/GRIP1. AIB1 was initially found to be amplified in breast cancer , but was later also found to be amplified in other cancers , including ovarian cancers [15, 16], endometrial carcinomas , pancreatic cancers  and prostate cancer . In mice models, AIB1 overexpression is linked to high frequency of tumorigenesis in mammary gland pituitary, uterus and lung [20, 21], and AIB1 knockdown would lead to inhibition of mammary gland tumorigenesis induced by oncogene HER2/neu. These observations indicate that AIB1 plays a key role in the development and progression of several different cancers. AIB1 acts as a transcriptional coactivator of nuclear receptors such as estrogen receptor alpha (ERα), and recruits secondary coactivators, including p300/CBP to facilitate the transcription of target genes . Moreover, AIB1 also plays a role in epidermal growth factor receptor (EGFR) signaling and insulin-like growth factor (IGF) signaling .
AIB1 is tightly regulated, especially by post-translational modification, which includes phosphorylation, acetylation, methylation, ubiquitination and sumoylation [25–27]. Post-translational modification of AIB1 can either up-regulate or down-regulate its protein or activity level. For examples, dephosphorylation of AIB1 by several phosphatases pyridoxal phosphate phosphatase (PDXP), protein phosphatase 1 (PP1), and protein phosphatase 2A (PP2A) can suppress its transcriptional activity , whereas ubiquitination of AIB1 can lead to its degradation . Among the three enzymes (E1, E2 and E3) that catalyze the ubiquitination of proteins, only E3 ubiquitin ligases physically interact with their substrates, and therefore confer some degree of specificity. Several E3 ubiquitin ligases are known to associate with the ubiquitination of AIB1, and these are E6-associated protein (E6-AP), F-box and WD repeat domain-containing 7 alpha (Fbw7α) and speckle-type POZ protein (SPOP) [30–32]. Among them, Fbw7α has been widely investigated. It is a classical E3 ubiquitin ligase of AIB1, and it controls numerous cellular processes, including cell-cycle progression, cell proliferation and differentiation through degrading a set of well-known oncoproteins such as c-myc and cyclin E in addition to AIB1 .
In this study, we showed that PTEN could act as a negative regulator of AIB1 through decreasing its protein stability, leading to suppression of its transcriptional activity and oncogenic function. We also presented evidence to show that such regulation of AIB1 by PTEN occurred via a mechanism that involved Fbw7α.