AIB1, a coactivator for nuclear receptors and other transcription factors, is involved in breast cancer development and progression. Overexpression of both AIB1 and HER2/neu (HER2) results in tamoxifen (Tam) resistance in clinical and experimental breast cancer. We hypothesized that HER2 signaling, via its downstream kinase Akt, leads to phosphorylation and activation of AIB1, which may then contribute to development of Tam resistance by reducing its antagonist activity.
We have previously shown that Akt synergizes with AIB1 to enhance estrogen- and Tam-induced estrogen receptor (ER)-dependent transcriptional activity. This synergy is mainly mediated by Akt phosphorylation of AIB1 on serine 967, which is located between the nuclear receptor and the CBP/p300 interacting domains. We showed that this serine residue was phosphorylated specifically by Akt both in vitro and in vivo, including in both acquired and de novo Tam-resistant xenograft models that are associated with increased Akt signaling. More recent data showed that serine 967 of AIB1 is phosphorylated in Tam-resistant MCF7 tumors, and that this phosphorylation is stable in the resistant cells. By using immunoprecipitation and Western blot analysis, in ER positive breast tumors from patients, 90% of tumors were positive for total AIB, while AIB1 phosphorylation was detectable in 60% of tumors. Phosphorylated AIB1 was positively correlated with total and phosphorylated HER2 (Tyrosine 1248) (p=0.004 and p=0.0008 respectively, Fisher's exact test), implying that phophorylation of serine 967 of AIB1 may be stimulated by HER2 in these AIB1 positive tumors. Serine 967 of AIB1 was also phosphorylated in breast cancer cell lines, including both basal (HCC1954, BT20 and SUM190PT) and luminal (T47D, ZR7530, MDAMB361, and UACC812) subtypes, in which HER2 (except BT20) and Akt were activated .
Taken together, Akt phosphorylation of AIB1 serine 967 appears important for AIB1 to function as an ER coactivator and regulator of breast cancer proliferation, and for Tam agonistic activity. Thus phosphorylation at serine 967 of AIB1 may be an essential factor required for Tam resistance as well as for tumor growth independent of ER. Additional regulatory roles of serine 967 in AIB1 function are currently under investigation.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3021.
- ©2009 American Association for Cancer Research.