KLF17 attenuates estrogen receptor α-mediated signaling by impeding ERα function on chromatin and determines response to endocrine therapy

Luminal-like breast cancer expressing estrogen receptor alpha (ER alpha) is among the aggressive breast tumor subtypes and shows poor prognosis. KLF17 plays a key role in breast cancer inhibition. However, the underlying mechanisms by which KLF17 control breast cancer progression remains unknown. Here, we show that KLF17 antagonizes ER alpha-dependent signaling to suppress breast cancer progression. KLF17 alters ER alpha-binding pattern throughout the genome and co-localizes with ER alpha on chromatin. Mechanistically, KLF17 forms a complex with ERa that interferes with ERa binding on chromatin and thereby attenuates ERa-dependent pathway. KLF17 increases the methylation status of ERE target promoters by recruiting transcriptional corepressor N-CoR/HDAC1 complex and prevents RNA polymerase II binding to suppress ER alpha-dependent transcriptional activation. Importantly, KLF17 preoccupies a subset of ERE target gene promoters and inhibits interaction of ER alpha with chromatin. Conversely, estrogen signaling suppresses KLF17 transcription via ER alpha/HDAC1-dependent mechanism. KLF17 expression negatively correlates with ERa target genes in multiple breast cancer samples. Enhanced KLF17 expression sensitizes ER alpha-positive breast cancer cells to endocrine therapy. KLF17 expression is downregulated in luminal breast cancer subtypes and is associated with poor survival rates in breast cancer patients. Taken together, these results indicate that KLF17-ER alpha interaction plays a potential role in inhibition of ER alpha-dependent breast cancer progression and suggests an improved strategy for treatment of ER alpha-positive breast cancer patients. (C) 2016 Elsevier B.V. All rights reserved.