High Expression of BCAR1 by Circulating Tumor Cells and Tumor Tissues Is Predictive of a Poor Prognosis of Early-Stage Lung Adenocarcinoma Potentially Due to Regulation of Epithelial-Mesenchymal Transition

Objective: To clarify the clinical significance of breast cancer anti-estrogen resistance protein 1 (BCAR1) expression in circulating tumor cells (CTCs) in the peripheral blood and tumor tissues in patients with early stage lung adenocarcinoma (ES-LUAD).

Methods: The study cohort included 60 patients with stage I LUAD (50 IA and 10 IB) who underwent surgery from November 2015 to November 2018 and 31 healthy controls. The expression levels of BCAR1 and markers of epithelial-mesenchymal transition (EMT) in peripheral blood CTCs were detected using CanPatrol^TM technology before surgery, and immunohistochemical analysis was used to detect BCAR1 expression in tumor tissues collected from 40 patients. The predictive power of BCAR1 expression in CTCs and tumor tissues on disease-free survival (DFS) was analyzed. The Cancer Genome Atlas (TCGA) database was used to study BCAR1 expression and overall survival as validation. The Gene Expression Profiling Interactive Analysis online tool was used to analyze the correlations between the expression levels of BCAR1 and EMT molecular markers.

Results: Both the number and detection rates of BCAR1-negative CTCs and BCAR1-positive CTCs in peripheral blood of lung cancer patients were significantly higher as compared with healthy controls (p < 0.05). BCAR1-positive CTCs more commonly co-expressed both epithelial and mesenchymal markers. Kaplan-Meier analysis demonstrated that patients with BCAR1(++) CTCs in peripheral blood before surgery were more prone to recurrence or metastasis after 2 years. COX analysis showed that patients with higher abundance of BCAR1(++) CTCs had a poorer prognosis (hazard ratio [HR] = 1.712, 95% confidence interval [CI] = 1.077-2.272, p = 0.023). Furthermore, high BCAR1 expression in tumor tissues was predictive of a poor prognosis (HR = 2.654, 95% CI = 1.239-5.686, p = 0.012), as validated by TCGA database (HR = 2.217, 95% CI = 1.069-4.595, p = 0.032). In addition, BCAR1 expression in LUAD tissues from TCGA was significantly positively correlated with the expression of both epithelial markers (e.g., ck8/18/19) and mesenchymal markers (e.g., vimentin and twist).

Conclusion: BCAR1 may have a "dual impact" on EMT markers in tumor tissues and CTCs due to micro-environmental disparities, resulting in important clinical significance, which can potentially guide accurate treatment of LUAD.