Homeobox transcription factor muscle segment homeobox 2 (Msx2) correlates with good prognosis in breast cancer patients and induces apoptosis in vitro

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.

The manufacture and assessment of tissue microarrays: suggestions and criteria for analysis, with breast cancer as an example

“…However, data on core loss in the literature is surprisingly poor, with many papers citing the final number of cases from their TMA series, but not the percentage of cores lost 26–28. Core losses of 2%,29 8%30 and 12%31 are reported, but much larger losses of up to 55% of an original cohort ‘primarily to core loss’32 have been recorded. It should be noted that core loss can occur at various TMA levels and, therefore, the number of available cores to score may vary for each antibody within the same TMA cohort.…”

Immunohistochemical expression of homeoproteins Six1 and Pax3 in breast phyllodes tumours correlates with histological grade and clinical outcome

“…The significance and mechanism of elevated expression of homeoprotein in the epithelium of lower grade PTs were unclear. However, one study reported that elevated expression of Msx2 homeoprotein was able to induce apoptosis of tumour cells in vitro . In PTs, it is possible that the activation of downstream signalling from the epithelial component affected the stromal component in a paracrine manner, thus keeping the epithelial–stromal architecture in balance in the lower‐grade tumours.…”

Anti-proliferative effect of Flos Albiziae flavonoids on the human gastric cancer SGC-7901 cell line

“…Apoptosis plays an important role in controlling cell numbers in a number of physiological and growth processes, in tissue homeostasis, and in the regulation of the immune system, whereas insufficient apoptosis is an integral part of cancer development (19). Recently, inducers of apoptosis have been used in cancer therapy, and activation of apoptotic pathways is a key mechanism by which cytotoxic drugs kill tumor cells, which is now considered as an important method of assessment for the clinical effectiveness of many antitumor drugs (20).…”