The Cell Fate Determination Factor DACH1 Is Expressed in Estrogen Receptor-α–Positive Breast Cancer and Represses Estrogen Receptor-α Signaling

Abstract

The Dachshund (dac) gene, initially cloned as a dominant inhibitor of the Drosophila hyperactive EGFR mutant ellipse, encodes a key component of the cell fate determination pathway involved in Drosophila eye development. Analysis of more than 2,200 breast cancer samples showed improved survival by some 40 months in patients whose tumors expressed DACH1. Herein, DACH1 and estrogen receptor-α (ERα) expressions were inversely correlated in human breast cancer. DACH1 bound and inhibited ERα function. Nuclear DACH1 expression inhibited estradiol (E2)-induced DNA synthesis and cellular proliferation. DACH1 bound ERα in immunoprecipitation-Western blotting, associated with ERα in chromatin immunoprecipitation, and inhibited ERα transcriptional activity, requiring a conserved DS domain. Proteomic analysis identified proline, glutamic acid, and leucine rich protein 1 (PELP1) as a DACH1-binding protein. The DACH1 COOH terminus was required for binding to PELP1. DACH1 inhibited induction of ERα signaling. E2 recruited ERα and disengaged corepressors from DACH1 at an endogenous ER response element, allowing PELP1 to serve as an ERα coactivator. DACH1 expression, which is lost in poor prognosis human breast cancer, functions as an endogenous inhibitor of ERα function.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…DACH1 represses ERα signaling by blocking coactivator-receptor interactions, i.e., PELP1-ERα interactions, which results in the increase in the relative abundance of HDAC1 on ERα target genes to suppress ERα transcription. Expression of ERα and DACH1 is also reported to be inversely correlated in human breast cancers [198]. Depletion of endogenous prohibitin (PHB), a tumor suppressor, is shown to enhance the expression of ERα target genes in MCF7 breast cancer cells.…”

“…Similarly, low expression of scaffold attachment factors, such as SAFB1 and SAFB2, is associated with poor overall survival in patients who have not received adjuvant therapy [197]. Dachshund homolog 1 (DACH1), a cell fate decision factor, is a novel corepressor of ERα [198]. DACH1 represses ERα signaling by blocking coactivator-receptor interactions, i.e., PELP1-ERα interactions, which results in the increase in the relative abundance of HDAC1 on ERα target genes to suppress ERα transcription.…”

The retinal determination genedachshundrestricts cell proliferation by limiting the activity of the Homothorax-Yorkie complex

“…Moreover, DACH1 has been shown to interact with a DNA-binding sequence that resembles the FOX (Forkhead boxcontaining protein) binding site , but also counteracts the effect of Ras, ErbB2 and Myc on the cyclin D1 promoter through binding to c-Jun or CREB (Sunde et al, 2006;Wu et al, 2006Wu et al, , 2007. Because DACH1 interacts with the nuclear receptor co-repressor (NCoR), mSin3A and histone deacetylases (HDACs) (Popov et al, 2009;Song et al, 2003;Tskvitaria-Fuller et al, 2003;Wu et al, 2003a,b), the interaction of Dac with Hth might bring general co-repressors of the transcriptional machinery to the ban enhancers.…”

Cell Fate Determination Factor Dachshund Reprograms Breast Cancer Stem Cell Function

“…Initially cloned as a dominant inhibitor of Ellipse in Drosophila, the mammalian DACH1 gene inhibits breast cancer cellular DNA synthesis and proliferation in cultured cells (13). DACH1 regulates gene expression of target genes in part through interacting with DNA-binding transcription factors (c-Jun, Smads, Six, and ER␣) and in part through intrinsic DNA binding (13,14,16). Recent studies have demonstrated that DACH1 conveys intrinsic DNA sequence-specific binding properties through elements resembling binding sites for the Forkhead family of proteins (17).…”