**4. AIB1 potentiates hormone receptor signaling**

Estrogen, progesterone and androgen receptors (ER, PR, AR) are nuclear steroid receptors, which play a major role in sexual development and reproduction. Upon binding to their ligands, these receptors dimerize and translocate to the nucleus. They act as transcription factors by binding directly to unique DNA sequences termed response elements. Subsequently, histone modifying enzymes and transcriptional co-regulators are recruited to activate target gene transcription. AIB1 has been shown to directly interact with ER, PR and AR via its LXXLL motifs [39, 40]. There are two classes of estrogen receptors; ERα and ERβ. AIB1 binds and enhances ERα receptor-stimulated gene transcription in a ligand-dependent manner [6]. Upon binding to ERα, AIB1 recruits chromatin-remodeling histone acetyl-transferases enzymes and thus increases ERα transcriptional activity. On the other hand, AIB1 can regulate ERα protein levels when bound to estradiol (E2). AIB1 recruits ubiquitin-proteasome complex to the ligand bound ERα leading to its degradation. Studies have shown that when AIB1 levels are reduced, ERα levels are stabilized [41]. In AIB1−/− mice, delays in puberty and mammary gland development as well as aberrant reproductive functions have been reported [5]. Similar observations are seen in both PR−/− and ER−/− mice emphasizing the essential role of AIB1 in ER and PR dependent functions. In breast cancer, AIB1 potentiates the development of hormone-dependent tumors and contributes to antiestrogen resistance [42, 43]. Lacking the inhibitory domain, AIB1Δ4 isoform has been shown to potentiate ER and PR transcription activity to a much greater extent than AIB1 [20]. In breast tumor samples, the association between AIB1 level and both ER and PR levels has not been clearly determined. One study showed that amplification of AIB1 in breast cancer correlates with high expression of ER and PR [44]. Yet another study showed that overexpression of AIB1 in breast cancer samples was associated

with loss of both ER and PR expression [45]. Moreover, AIB1 strongly binds AR and co-activates its target gene transcription. In prostate cancer, AIB1 is shown to be overexpressed and its levels correlate with higher tumor grade and increased disease recurrence but did not correlate with serum PSA levels [46]. Several studies have established AIB1 as a preferred coactivator for hormone-activated AR. Mutations in AR that alter its binding potency to AIB1 has been found in prostate cancer patients, suggesting an oncogenic role of AIB1 in prostate cancer [40].
