Abstract
IntroductionMelanoma differentiation associated gene-7 (MDA-7), also known as interleukin (IL)-24, is a tumour suppressor gene associated with differentiation, growth and apoptosis. However, the mechanisms underlying its anti-neoplastic activity, tumour-specificity and efficacy across a spectrum of human cancers have yet to be fully elucidated. In this study, the biological impact of MDA-7 on the behavior of breast cancer (BC) cells is evaluated. Furthermore, mRNA expression of MDA-7 is assessed in a cohort of women with BC and correlated with established pathological parameters and clinical outcome.MethodsThe human BC cell line MDA MB-231 was used to evaluate the in-vitro impact of recombinant human (rh)-MDA-7 on cell growth and motility, using a growth assay, wounding assay and electric cell impedance sensing (ECIS). Localisation of MDA-7 in mammary tissues was assessed with standard immuno-histochemical methodology. BC tissues (n = 127) and normal tissues (n = 33) underwent RNA extraction and reverse transcription, MDA-7 transcript levels were determined using real-time quantitative PCR. Transcript levels were analyzed against tumour size, grade, oestrogen receptor (ER) status, nodal involvement, TNM stage, Nottingham Prognostic Index (NPI) and clinical outcome over a 10 year follow-up period.ResultsExposure to rh-MDA-7 significantly reduced wound closure rates for human BC cells in-vitro. The ECIS model demonstrated a significantly reduced motility and migration following rh-MDA-7 treatment (p = 0.024). Exposure to rh-MDA-7 was only found to exert a marginal effect on growth. Immuno-histochemical staining of human breast tissues revealed substantially greater MDA-7 positivity in normal compared to cancer cells. Significantly lower MDA-7 transcript levels were identified in those predicted to have a poorer prognosis by the NPI (p = 0.049) and those with node positive tumours. Significantly lower expression was also noted in tumours from patients who died of BC compared to those who remained disease free (p = 0.035). Low levels of MDA-7 were significantly correlated with a shorter disease free survival (mean = 121.7 vs. 140.4 months, p = 0.0287) on Kaplan-Meier survival analysis.ConclusionMDA-7 significantly inhibits the motility and migration of human BC cells in-vitro. MDA-7 expression is substantially reduced in malignant breast tissue and low transcript levels are significantly associated with unfavourable pathological parameters, including nodal positivity; and adverse clinical outcomes including poor prognosis and shorter disease free survival. MDA-7 offers utility as a prognostic marker and potential for future therapeutic strategies.
Highlights
Melanoma differentiation associated gene-7 (MDA-7), known as interleukin (IL)-24, is a tumour suppressor gene associated with differentiation, growth and apoptosis
The electric cell impedance sensing (ECIS) model demonstrated a significantly reduced motility and migration following rh-MDA-7 treatment (p = 0.024)
Lower MDA-7 transcript levels were identified in those predicted to have a poorer prognosis by the Nottingham Prognostic Index (NPI) (p = 0.049) and those with node positive tumours
Summary
Melanoma differentiation associated gene-7 (MDA-7), known as interleukin (IL)-24, is a tumour suppressor gene associated with differentiation, growth and apoptosis. Melanoma differentiation associated gene-7 (MDA-7), known as interleukin (IL)-24, is an intriguing member of the class II/IL-10 cytokine family [1]. This novel tumour suppressor gene was initially identified from of the malignant phenotype and terminal differentiation [6]. Specific anti-tumour activity has been established in a range of human tumour xenograft models and recently in several earlyphase clinical trials involving patients with advanced solid cancers [10,11,14,15]. MDA-7 is emerging as a differentiation, growth and apoptosis associated gene with potential utility for the gene-based therapy of several human cancers [4]
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