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TOX3 is Expressed in Mammary ER Positive Epithelial Cells and Regulates a Subset of ER Target Genes in a Ligand-Independent Manner in Luminal Breast Cancer

ABSTRACT: To assess how the TOX3 nuclear protein can modulate gene expression in luminal epithelial cells, MCF7 cells were transfected with a TOX3 expression vector or vector control. In both instances, GFP was coexpressed, allowing isolation of transfected cells by flow cytometry before transcriptome analysis. Experiments were carried out under estrogen depleted conditions, and cells isolated 48 hours after transfection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57856 | GEO | 2014/12/01

SECONDARY ACCESSION(S): PRJNA248263

REPOSITORIES: GEO

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Project description: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.

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TOX3 is Expressed in Mammary ER Positive Epithelial Cells and Regulates a Subset of ER Target Genes in a Ligand-Independent Manner in Luminal Breast Cancer

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