Abstract 4978: FOXP3 up-regulates p21 expression in breast cancer: Evidence for tumor suppressor

Abstract

Abstract FOXP3 is the first X-linked breast cancer suppressor gene that works at least in part by repression of oncogenes, including HER-2 and SKP2. Since FOXP3 is also known as a transcription activator, we investigated the possibility that FOXP3 may induce expression of tumor suppressor genes. p21 loss has been implicated in conferring oncogenic activity to known tumor suppressor gene KLF4 and cancer drug tamoxifen. Regulators of p21, therefore, play critical roles in tumorigenesis. Here, we report that X-linked tumor suppressor FOXP3 is essential for p21 expression in normal epithelia and that lack of FOXP3 is associated with p21 down-regulation in breast cancer samples. Among 62 primary breast cancer samples tested, a strong association between FOXP3 down-regulation and lack of p21 was observed. Moreover, siRNA silencing of FOXP3 in primary human mammary epithelial cells leads to a dramatic reduction in expression of p21, which demonstrates an important role of FOXP3 in maintaining expression of p21 in normal breast epithelial cells. In breast cancer cell line MCF-7, an inducible expression of FOXP3 is associated with induction of p21. Since silencing p21 reduced the efficacy of FOXP3-mediated growth inhibition, the induced expression of p21 contributes to growth inhibition by FOXP3. A specific FOXP3 binding site in the intron 1, which is associated with acetylated histone H3, is essential for p21 induction by FOXP3. FOXP3 specifically inhibited binding of histone deacetylase 2 (HDAC2) and HDAC4 to the site and increased local histone H3 acetylation. Short hairpin RNA silencing of either HDAC2 or HDAC4 is sufficient to induce p21 expression. Our data provides a novel mechanism for transcription activation by FOXP3 and a genetic mechanism for lack of p21 in a large proportion of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4978.