The Tra2-dependent way of alternative splicing: Findings and implications in breast cancer

Introduction: Tra2, member of the extended family of serine-argenine-rich (SR) splicing factors, regulates alternative splicing of exons with C/A-rich enhancer sequences. Besides the CD44 gene which undergoes extensive alternative splicing of at least 10 variable exons, other biological important genes, like VEGF, prolactin- estrogen- and insulin receptor, BRCA2 and Syk are alternatively spliced and contain these C/A-rich sequences. Recently, we demonstrated that alternative exon v4 inclusion is increased upon over-expression of the DNA and RNA binding protein YB-1 and Tra2 in a mouse model of breast cancer development. Material and Methods: In this study we investigated expression levels of TRa2 in a matched pair analysis of tumor samples and normal tissues of patients with invasive breast cancer by Western Blot and RT-PCR analysis. In addition, we analyzed the alternative splicing of the above mentioned tumor biological important genes in the same paradigm. Results: Western Blot and RT-PCR revealed a marked induction of Tra2-beta in adenocarcinomas of the breast in comparison to physiological tissue samples of the same patient. The splicing analysis showed in parallel an dramatically changed alternative splicing in the investigated genes with C/A-rich enhancers in tumors versus matched physiological breast tissue. Conclusions: Our results suggest that involvement of Tra2 in exon recognition and alternative splicing may be important to over-expression of alternatively spliced genes with potential functional consequences in invasive breast cancer leading to tumor progression and metastasis.