Abstract 4855: KLLN, which shares a bidirectional promoter with PTEN, is an AR-regulated tumor suppressor, and induces p53-dependent and -independent apoptosis in breast cancer

Abstract

Abstract 70% of breast cancer patients are diagnosed after menopause where the ovaries cease androgen production. Maintaining functional androgen receptor (AR) has been reported to correlate with good prognosis and better survival among breast cancer patients. We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells. However, the mechanism of AR's anti-tumor effect in breast cancer is still not fully understood. KLLN is a newly identified gene whose function has never been studied in tumorigenesis. KLLN and tumor suppressor gene PTEN, both located in 10q23.31, share the same promoter region but are transcribed in opposite directions. To perform in silico comparisons of KLLN expression between normal breast and breast cancer tissues, we selected 56 normal breast and 1170 tumor tissues from patients without exposure to any treatment using publicly available whole genome transcriptome datasets. We found that KLLN is significantly downregulated in breast carcinomas and that loss of KLLN expression is associated with increasing histological grade in invasive carcinomas. By using MCF-7 and MDA-MB-453 breast cancer cell lines as our models, we show that AR activates this bi-directional promoter, resulting in the upregulation of both KLLN and PTEN expression. For the first time, we identified KLLN as an AR-activated tumor suppressor, inhibiting breast cancer cell proliferation and suppressing tumor cell invasiveness in both cell lines. In MCF-7 cells, overexpression of KLLN directly activates TP53 expression as a transcription activator, accompanied by significant increase of PARP cleavage and apoptosis. We also found that KLLN could promote TP73 expression in both MCF-7 (p53-wildtype) and MDA-MB-453 (p53-null) cells at the transcriptional level, resulting in p53-independnt apoptosis. Therefore, we discovered a new pathway, which mediates AR-induced growth inhibition and apoptosis in breast cancer cells. Our study also indicates KLLN as a potential prognostic marker and novel therapy target for breast carcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4855. doi:1538-7445.AM2012-4855