Decreased Usage of Specific Scrib Exons Defines a More Malignant Phenotype of Breast Cancer With Worsened Survival

• Proteome analysis of breast tumors shows loss of C-terminal Scribble sequences.
• Distinct pattern of SCRIB exon usage revealed by tumor RNA-seq analysis.
• SCRIB exon usage patterns correlate with long-term survival in breast cancer.
• Human Scribble interacts with Numa1, a protein which regulates the positioning of the mitotic splindle.We report experimental evidence showing that human breast tumors exhibit a distinct SCRIB exon usage preference that leads to overexpression of conserved N-terminal domains and loss of C-terminal sequences that are involved in the fine tuning of the cell cycle. This is specific for breast tumors and could potentially open new ways for developing stratified therapies for breast cancer.

SCRIB is a polarity regulator known to be abnormally expressed in cancer at the protein level. Here we report that, in breast cancer, an additional and hidden dimension of deregulations exists: an unexpected SCRIB exon usage pattern appears to mark a more malignant tumor phenotype and significantly correlates with survival. Conserved exons encoding the leucine-rich repeats tend to be overexpressed while others are underused. Mechanistic studies revealed that the underused exons encode part of the protein necessary for interaction with Vimentin and Numa1, a protein which is required for proper positioning of the mitotic spindle. Thus, the inclusion/exclusion of specific SCRIB exons is a mechanistic hallmark of breast cancer, which could potentially be exploited to develop more efficient diagnostics and therapies.