Creative Biogene

The role of orphan nuclear receptor DAX-1 (NR0B1) in human breast cancer cells: expression, proliferation and metastasis

Authors: Dishington, Erin;
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Abstract

The orphan nuclear hormone receptor DAX-1 (Dosage Sensitive Sex Reversal, Adrenal Hypoplasia Congenita on the X Chromosome, gene 1) plays an important role in the development of adrenal and gonadal tissues and functions as a global negative-regulator of steroidogenesis. In addition, it is known to be involved in several diseases including some cancers. Herein, we describe our examination of the role of DAX-1 in breast cancer, specifically its influence on proliferation and metastasis and its expression during progressive stages of disease. In an effort to understand how DAX-1 influences breast cancer cell proliferation and metastasis, we used MCF7 breast cancer cells and MCF10A normal breast cells and manipulated their DAX-1 expression to increase DAX-1 expression by adenovirus infection in MCF7 cells, or knockdown expression of DAX-1 through the use of RNAi in MCF10A cells. We found a trend toward increased cell proliferation when DAX-1 expression was knocked down, and decreased proliferation when DAX-1 is overexpressed. In addition, we looked at the influence of DAX-1 on breast cancer cell proliferation when the estrogen receptor a (ERa) activity is inhibited by the antagonist, Fulvestrant. To gain a better understanding of the transcriptional role of DAX-1 in breast cancer, we utilized PCR arrays to analyze changes in gene expression in the presence of DAX-1. We identified several genes with roles in breast cancer, estrogen receptor signaling and metastasis whose expression was significantly influenced by overexpression of DAX-1 in MCF7 cells. To investigate expression of DAX1 through progressive stages of disease we utilized IHC and bioinformatics techniques. We found DAX1 to be expressed more frequently and at higher levels at earlier stages of breast cancers and at very low levels regardless of stage in hormone receptor-positive (ER and PR) patients. Through these studies, we hypothesize that DAX-1 has the potential to be utilized clinically as biomarker for predicting disease progression and for tailoring more personalized treatment plans. There may even be a role for DAX-1 as a possible therapeutic for later stage or hormone receptor-positive patients.