| Summary: | 博士 === 國立陽明大學 === 臨床醫學研究所 === 107 === Background/aims: About one third of breast cancer tumors are categorized as hormone receptor (HR)-negative subtype and do not respond to hormone therapy. The HR-negative breast cancers, including human epidermal growth factor receptor 2 (HER2) positive or triple negative breast cancer (TNBC), are found to carry worse survival outcome but the critical factors mediating relapse or survival remain controversial. The aims of this study were to investigate the prognostic factors involved in recurrence of HR-negative breast cancer, and to evaluate whether the interpretation of biomarkers may predict the efficacy of medical therapy.
Subjects & Methods: Under the approval of Institutional Review Board of Taipei Veterans General Hospital, breast cancer tissues were used for oligonucleotides microarray analysis (recurrence or non-recurrence) in TNBC and for HER2 immunostaining or in situ hybridization in HER2-positive breast cancer. The tumor samples of patients with HER2 overexpression were grouped into IHC 3+ and IHC 2+/ISH+ to analyze the correlation to treatment outcome. The MDA-MB-231 and human endothelial HUVEC lines were used for functional studies such as migration assay, Western blot and real-time PCR.
Results: Through oligonucleotides microarray analysis, brain-derived neurotrophic factor (BDNF) was identified as a biomarker to differentiate recurrent TNBC from non-recurrent TNBC. The up-regulation of BDNF-TrkB gene expression enhanced the migration ability of both MDA-MB-231 cells and HUVEC. Ingenuity pathway analysis (IPA) of MDA-MB-231 cells showed BDNF as a key factor to regulate a network made up of metalloproteases and calmodulin. In addition, overexpression of TrkB, but not of BDNF, is significantly associated with a poor survival outcome for TNBC patients. In HER2-positive breast cancer, both HER2 copy numbers and HER2 ISH ratios of the IHC 3+ group were significantly higher than those of the IHC 2+/ ISH+ group. The outcomes of IHC 3+ patients were significantly better than those of IHC 2+/ISH+ patients. HER2 copy numbers of ≥8 represented the best prognostic value, and it was chosen to be the cut-off value. The reflex ISH for IHC 2+ patients with high HER2 copy numbers (≥8) predicted a better overall survival than that for those with low HER2 copy numbers. The prognosis of IHC 3+ and IHC 2+/ISH+ patients is different according to the level of HER2 ISH ratios or copy numbers.
Conclusion: We conclude that our results provide novel perspectives to review the importance of HER2 testing from its ability to predict the efficacy of treatment and to find a potential biomarker, BDNF, participating in the process of early metastasis in HR-negative breast cancer.
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