Endothelial Mesenchymal Transition Gene Signatures in Metastatic Early Stage Breast Cancer
Pingchuan Zhang, Jian He, Riyam Zreik, Arundhati Rao. Scott and White Memorial Hospital, Temple, TX; Texas A&M University Health Science Center, Temple, TX
Background: The etiology of distant metastasis in early stage breast cancer patients remains unclear. Recent studies have demonstrated that dynamic interactions between the neoplastic cells and the tumour microenvironment can play an important role in metastasis of many malignant neoplasms. We performed multivariate analysis in an early stage breast cancer cohort and identified matched specimens with and without metastasis to identify further discriminators. A gene profiling study involving mesenchymal transition (EMT) genes was performed to search for genetic alterations in early stage HER2 negative breast cancer patients.
Design: Retrospective chart review of patients diagnosed with Stage I and II Breast Cancer from 2001 to 2003 was performed. Multivariate analysis Covariates evaluated included age, Nottingham combined grade, Estrogen receptor (ER) and progesterone receptor (PR) status. Cox Proportional Hazards (PH) regression modeling and Kaplan Meier Survival Curves were used to determine independent risk factors of tumor free survival. Based on the results, we matched cases with distant metastasis and without metastasis by stage, age, ethnicity, ER/PR, and HER2 status. Total RNA was extracted from micro-dissected formalin fixed paraffin embedded tissue using the RNeasy extraction kit. RNA was converted to cDNA using RT^2 PreAMP cDNA Synthesis Kit (Qiagen, CA, USA). cDNAs were analyzed for EMT gene expression profiling, using RT^2 Profiler PCR ARRAY (Rotor-Gene Format) Human EMT kit on the Rotor-Gene Q (Qiagen, CA, USA).
Results: With 10 year follow-up, of 366 stage I and II breast cancer patients, 28 patients were identified with distant metastasis. Stage, age, ethnicity, ER/PR status persisted as important risk factors. EMT gene expression profiling study revealed seven genes with at least 170-fold overexpression in metastatic cancers. The top 3 most overexpressed genes are AKT1, JAG1 and SMAD2. The overexpressed genes were involved in core signaling pathways of tumor genesis including PIK3CA signaling, Wnt/Notch signaling and TGF-β signaling etc. These results may support these signaling pathways and processes aberrations also contribute to breast cancer metastasis.
Conclusions: Our study suggests upregulation of EMT gene expression plays an important role in metastasis in early stage breast cancer patients. These results may support these signaling pathways and processes aberrations also contribute to breast cancer metastasis. Further investigation in a larger cohort to verify the results is needed.
Wednesday, March 6, 2013 9:30 AM
Poster Session V # 21, Wednesday Morning