Abstract
BackgroundThe triple negative breast cancer (TNBC) paradox marks a major challenge in the treatment-decision making process. TNBC patients generally respond better to neoadjuvant chemotherapy compared to other breast cancer patients; however, they have a substantial higher risk of disease recurrence. We evaluated the expression of the tumor-associated antigen PReferentially Antigen expressed in MElanoma (PRAME) as a prognostic biomarker in breast cancer and explored its role in cell migration and invasion, key hallmarks of progressive and metastatic disease.MethodsTCGA and GTeX datasets were interrogated to assess the expression of PRAME in relation to overall and disease-free survival. The role of PRAME in cell migration and invasion was investigated using gain- and loss-of-function TNBC cell line models.ResultsWe show that PRAME promotes migration and invasion of TNBC cells through changes in expression of E-cadherin, N-cadherin, vimentin and ZEB1, core markers of an epithelial-to-mesenchymal transition. Mechanistic analysis of PRAME-overexpressing cells showed an upregulation of 11 genes (SNAI1, TCF4, TWIST1, FOXC2, IL1RN, MMP2, SOX10, WNT11, MMP3, PDGFRB, and JAG1) and downregulation of 2 genes (BMP7 and TSPAN13). Gene ontology analyses revealed enrichment of genes that are dysregulated in ovarian and esophageal cancer and are involved in transcription and apoptosis. In line with this, interrogation of TCGA and GTEx data demonstrated an increased PRAME expression in ovarian and esophageal tumor tissues in addition to breast tumors where it is associated with worse survival.ConclusionsOur findings indicate that PRAME plays a tumor-promoting role in triple negative breast cancer by increasing cancer cell motility through EMT-gene reprogramming. Therefore, PRAME could serve as a prognostic biomarker and/or therapeutic target in TNBC.
Highlights
The triple negative breast cancer (TNBC) paradox marks a major challenge in the treatment-decision making process
Antigen expressed in MElanoma (PRAME), otherwise known as cancer testis antigen 130 (CT130), melanoma antigen preferentially expressed in tumors (MAPE) and OIP4 (OPA-interacting protein 4) is a member of the cancer testis antigen (CTA) family
We found an increased expression of PReferentially Antigen expressed in MElanoma (PRAME) in cancer tissues compared to the corresponding normal tissues for the most common cancer types among women worldwide in addition to its well-known upregulation in melanoma (Fig. 1a)
Summary
The triple negative breast cancer (TNBC) paradox marks a major challenge in the treatment-decision making process. Breast cancer remains a major health burden worldwide, despite many improvements in diagnostics and development of a wide range of novel treatment options. Despite a complete pathological response in 30% of patients, the majority will relapse and develop brain and lung metastases within 3–5 years after diagnosis [5] These poor prospects justify the need for new targeted treatments for TNBC and validate the ongoing efforts to identify novel biomarkers for residual disease and metastasis. Several promising therapeutic agents are currently in clinical trial, including Poly (ADP-ribose) Polymerase (PARP) inhibitors, Src inhibitors, and antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents [6] None of these regimens are effective in treating all cancer cases and further studies are undertaken to identify subgroups of patients that may benefit more from targeted treatments. The search for biomarkers to predict the presence of minimal residual disease and the risk of metastasis remain the focus of many studies on triple negative breast cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
