P2-11-02: Brain-Derived Neurotrophic Factor Expression Is Associated with Poor Prognosis in Human Breast Cancer.

Abstract

Abstract Background: Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin superfamily of polypeptide growth factors whose physiological roles primarily relate to the development and function of the vertebrate nervous system. However, BDNF is also expressed in non-neuronal tissues and has been implicated in breast cancer, in addition to several other human malignancies, including: neuroblastoma, myeloma, ***ovarian, lung, prostate, hepato-cellular, pancreatic, head and neck squamous cell carcinomas and pulmonary carcinoid tumours. Although increased neurotrophin and cognate receptor expression have been demonstrated in breast cancer, the emerging role of BDNF in tumour biology and its utility as a novel biomarker have yet to be fully elucidated. In this study, the mRNA and protein expression of BDNF are evaluated in women with primary operable breast cancer in a well annotated cohort with extended follow-up. Methods: Breast cancer tissues (n=127) and normal/benign tissues (n=33) underwent RNA extraction and reverse transcription. Transcript levels of BDNF were determined using real-time quantitative PCR and protein expression was assessed using standardised semi-quantitative immuno-histochemical techniques. Expression levels in neoplastic tissues were compared with adjacent normal/benign samples and evaluated against conventional pathological parameters, including: tumour size, grade, nodal involvement, TNM stage, in addition to Nottingham Prognostic Index (NPI), disease free and overall survival over a 10 year follow-up period. Results: BDNF was found to be expressed in both normal breast tissue and breast cancer specimens. Significantly greater BDNF expression was identified in neoplastic cells, compared to normal mammary epithelial cells, by immuno-histochemical analysis. In keeping with this, higher mRNA transcript levels of BDNF were also found in breast cancers compared to normal samples (p=0.007). Increased BDNF transcript levels were found to be significantly associated with nodal positivity (p=0.047) and increased with NPI; NPI-1 vs. NPI-2 (p=0.009). Higher BDNF expression was significantly associated with local recurrence (p=0.0014), death from breast cancer (p=0.018) and poor prognosis overall (p=0.013), when compared to patients who remained disease free. Higher transcript levels were significantly associated with poorer overall survival (106 vs. 136 months, p=0.006) after a median follow up of 10 years. Conclusion: Neurotrophins and their receptors are increasingly being implicated as novel mediators of carcinogenesis in neuronal and non-neuronal tissues. BDNF is overexpressed in breast cancer and significantly associated with adverse pathological parameters, including nodal positivity and increasing NPI. Higher BDNF expression was significantly associated with poorer clinical outcomes, including local recurrence, death, poor prognosis and reduced overall survival. The present study adds to the literature in support of the oncogenic function of BDNF in breast cancer and is the first to quantitatively evaluate expression in a large cohort. BDNF expression may offer prognostic utility as a biomarker and further mechanistic studies are warranted to explore the potential for targeted therapeutic manipulation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-02.