Abstract
BackgroundDisseminated tumor cells (DTCs) can be detected using ultrasensitive immunocytochemical assays and their presence in the bone marrow can predict the subsequent occurrence of overt metastasis formation and metastatic relapse. Using expression profiling on early stage primary breast tumors, low IRX2 expression was previously shown to be associated with the presence of DTCs in the bone marrow, suggesting a possible role of IRX2 in the early steps of metastasis formation. The purpose of this study is to gain insights into the significance of IRX2 protein function in the progression of breast cancer.MethodsTo assess the physiological relevance of IRX2 in breast cancer, we evaluated IRX2 expression in a large breast cancer cohort (n = 1992). Additionally, constitutive IRX2 over expression was established in BT-549 and Hs578T breast cancer cell lines. Subsequently we analyzed whether IRX2 overexpression effects chemokine secretion and cellular motility of these cells.ResultsLow IRX2 mRNA expression was found to correlate with high tumor grade, positive lymph node status, negative hormone receptor status, and basal type of primary breast tumors. Also in cell lines low IRX2 expression was associated with mainly basal breast cancer cell lines. The functional studies show that overexpression of the IRX2 transcription factor in basal cell lines suppressed secretion of the pro-metastatic chemokines and inhibited cellular motility but did not influence cell proliferation.ConclusionOur results imply that the IRX2 transcription factor might represent a novel metastasis associated protein that acts as a negative regulator of cellular motility and as a repressor of chemokine expression. Loss of IRX2 expression could therefore contribute to early hematogenous dissemination of breast cancer by sustaining chemokine secretion and enabling mobilization of tumor cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1907-4) contains supplementary material, which is available to authorized users.
Highlights
Disseminated tumor cells (DTCs) can be detected using ultrasensitive immunocytochemical assays and their presence in the bone marrow can predict the subsequent occurrence of overt metastasis formation and metastatic relapse
We have recently shown that low Iroquois Homeobox 2 (IRX2) expression is associated with the presence of DTCs in the bone marrow of breast cancer patients [16], suggesting a possible role of IRX2 as a metastasis suppressor protein in breast cancer
Taken together these analyses clearly show that low IRX2 expression is correlated with different parameters of poor prognosis, indicating that loss of IRX2 expression is associated with less differentiated and more aggressive breast tumors
Summary
Disseminated tumor cells (DTCs) can be detected using ultrasensitive immunocytochemical assays and their presence in the bone marrow can predict the subsequent occurrence of overt metastasis formation and metastatic relapse. Using expression profiling on early stage primary breast tumors, low IRX2 expression was previously shown to be associated with the presence of DTCs in the bone marrow, suggesting a possible role of IRX2 in the early steps of metastasis formation. In osteosarcomas knockdown of IRX2 inhibits cell proliferation and invasion [11], and elevated IRX2 expression is correlated with worse outcome and age in infant acute lymphoblastic leukemia [12] These studies suggest a possible oncogenic function for the IRX2 protein, especially in malignant cells of mesenchymal origin. We have recently shown that low IRX2 expression is associated with the presence of DTCs in the bone marrow of breast cancer patients [16], suggesting a possible role of IRX2 as a metastasis suppressor protein in breast cancer
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