Abstract
BackgroundA breast cancer susceptibility locus has been mapped to the gene encoding TOX3. Little is known regarding the expression pattern or biological role of TOX3 in breast cancer or in the mammary gland. Here we analyzed TOX3 expression in murine and human mammary glands and in molecular subtypes of breast cancer, and assessed its ability to alter the biology of breast cancer cells.MethodsWe used a cell sorting strategy, followed by quantitative real-time PCR, to study TOX3 gene expression in the mouse mammary gland. To study the expression of this nuclear protein in human mammary glands and breast tumors, we generated a rabbit monoclonal antibody specific for human TOX3. In vitro studies were performed on MCF7, BT474 and MDA-MB-231 cell lines to study the effects of TOX3 modulation on gene expression in the context of breast cancer cells.ResultsWe found TOX3 expression in estrogen receptor-positive mammary epithelial cells, including progenitor cells. A subset of breast tumors also highly expresses TOX3, with poor outcome associated with high expression of TOX3 in luminal B breast cancers. We also demonstrate the ability of TOX3 to alter gene expression in MCF7 luminal breast cancer cells, including cancer relevant genes TFF1 and CXCR4. Knockdown of TOX3 in a luminal B breast cancer cell line that highly expresses TOX3 is associated with slower growth. Surprisingly, TOX3 is also shown to regulate TFF1 in an estrogen-independent and tamoxifen-insensitive manner.ConclusionsThese results demonstrate that high expression of this protein likely plays a crucial role in breast cancer progression. This is in sharp contrast to previous studies that indicated breast cancer susceptibility is associated with lower expression of TOX3. Together, these results suggest two different roles for TOX3, one in the initiation of breast cancer, potentially related to expression of TOX3 in mammary epithelial cell progenitors, and another role for this nuclear protein in the progression of cancer. In addition, these results can begin to shed light on the reported association of TOX3 expression and breast cancer metastasis to the bone, and point to TOX3 as a novel regulator of estrogen receptor-mediated gene expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1018-2) contains supplementary material, which is available to authorized users.
Highlights
A breast cancer susceptibility locus has been mapped to the gene encoding TOX3
TOX3 expression in mouse and human breast epithelium TOX3 expression has not been well defined in normal mammary epithelial cells
Together, our data suggest that TOX3 expression within the context of breast cancer is likely a tumor promoter rather than a strict tumor suppressor as had been proposed based on the decrease in TOX3 expression associated with disease risk [11]
Summary
A breast cancer susceptibility locus has been mapped to the gene encoding TOX3. Little is known regarding the expression pattern or biological role of TOX3 in breast cancer or in the mammary gland. In regard to the latter, genome wide association studies have been performed to identify novel disease risk alleles This approach has identified high frequency and low penetrance disease-associated single nucleotide polymorphisms (SNP) in a number of genes, including that encoding the HMG-box nuclear protein TOX high mobility group box family member 3 (TOX3) [2,3]. Despite this association, little is known concerning the expression pattern or biological functions of TOX3 in breast cancer or in mammary epithelial cells. The founding member of this protein family, TOX, plays a key role in the development of multiple aspects of the immune system [6,7,8] while the in vivo function of TOX3 remains to be identified
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