Abstract
IntroductionThe homeobox-containing transcription factor muscle segment homeobox 2 (Msx2) plays an important role in mammary gland development. However, the clinical implications of Msx2 expression in breast cancer are unclear. The aims of this study were to investigate the potential clinical value of Msx2 as a breast cancer biomarker and to clarify its functional role in vitro.MethodsMsx2 gene expression was first examined in a well-validated breast cancer transcriptomic dataset of 295 patients. Msx2 protein expression was then evaluated by immunohistochemistry in a tissue microarray (TMA) containing 281 invasive breast tumours. Finally, to assess the functional role of Msx2 in vitro, Msx2 was ectopically expressed in a highly invasive breast tumour cell line (MDA-MB-231) and an immortalised breast cell line (MCF10a), and these cell lines were examined for changes in growth rate, cell death and cell signalling.ResultsExamination of Msx2 mRNA expression in a breast cancer transcriptomic dataset demonstrated that increased levels of Msx2 were associated with good prognosis (P = 0.011). Evaluation of Msx2 protein expression on a TMA revealed that Msx2 was detectable in both tumour cell nuclei and cytoplasm. Cytoplasmic Msx2 expression was associated with low grade tumours (P = 0.012) and Ki67 negativity (P = 0.018). Nuclear Msx2 correlated with low-grade tumours (P = 0.015), estrogen receptor positivity (P = 0.038), low Ki67 (P = 0.005) and high cyclin D1 expression (P = 0.037). Increased cytoplasmic Msx2 expression was associated with a prolonged breast cancer-specific survival (P = 0.049), recurrence-free survival (P = 0.029) and overall survival (P = 0.019). Ectopic expression of Msx2 in breast cell lines resulted in radically decreased cell viability mediated by induction of cell death via apoptosis. Further analysis of Msx2-expressing cells revealed increased levels of p21 and phosphorylated extracellular signal-regulated kinase (ERK) and decreased levels of Survivin and the 'split ends' (SPEN) protein family member RBM15.ConclusionsWe conclude that increased Msx2 expression results in improved outcome for breast cancer patients, possibly by increasing the likelihood of tumour cell death by apoptosis.
Highlights
The homeobox-containing transcription factor muscle segment homeobox 2 (Msx2) plays an important role in mammary gland development
Msx2 mRNA expression is associated with good prognosis in a DNA microarray dataset Expression levels of Msx2 mRNA were analysed in a publicly available DNA microarray dataset derived from 295 primary invasive breast tumours [23]
Using a previously described method [25], 74 tumours were classified as expressing low levels of Msx2 mRNA, and 221 tumours were classified as expressing high levels of Msx2 mRNA, based on the log ratios of gene expression values
Summary
The homeobox-containing transcription factor muscle segment homeobox 2 (Msx2) plays an important role in mammary gland development. The aims of this study were to investigate the potential clinical value of Msx as a breast cancer biomarker and to clarify its functional role in vitro. Homeobox genes are thought to be involved in assimilating systemic signals into the precise local interactions required for correct morphogenesis [7,10]. Apoptosis plays an important role in this process, and the level of apoptosis in the mouse pubertal mammary gland is higher than at any other stage of development [12]. Msx expression is stimulated by both estradiol and progesterone, and the role of progesterone in promoting branching morphogenesis in the mouse mammary gland is thought to be mediated partially through Msx2 [14]. One of the few studies on Msx expression in human breast tissues reported a complicated regulation of Msx by steroid hormones: Msx could be either increased or decreased by steroid hormone treatment, depending on the estrogen/progesterone receptor (ER/PR) status and whether the breast tissue sample was normal or malignant [15]
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