Stage-specific changes in SR splicing factors and alternative splicing in mammary tumorigenesis

Oncogene. 1999 Jun 17;18(24):3574-82. doi: 10.1038/sj.onc.1202671.


Using a mouse model of mammary gland development and tumorigenesis we examined changes in both alternative splicing and splicing factors in multiple stages of mammary cancer. The emphasis was on the SR family of splicing factors known to influence alternative splicing in a wide variety of genes, and on alternative splicing of the pre-mRNA encoding CD44, for which alternative splicing has been implicated as important in a number of human cancers, including breast cancer. We observed step-wise increases in expression of individual SR proteins and alternative splicing of CD44 mRNA during mammary gland tumorigenesis. Individual preneoplasias differed as to their expression patterns for SR proteins, often expressing only a sub-set of the family. In contrast, tumors demonstrated a complex pattern of SR expression. Little difference was observed between neoplasias and their metastases. Alternative splicing of CD44 also changed through the disease paradigm such that tumors produced RNA containing a mixture of variable exons, whereas preneoplasias exhibited a more restricted exon inclusion pattern. In contrast, other standard splicing factors changed little in either concentration or splicing pattern in the same cells. These data suggest alterations in relative concentrations of specific splicing factors during early preneoplasia that become more pronounced during tumor formation. Given the ability of SR proteins to affect alternative processing decisions, our results suggest that a number of pre-mRNAs may undergo changes in alternative splicing during the early and intermediate stages of mammary cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alternative Splicing*
  • Animals
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Exons / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Hyaluronan Receptors / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / metabolism*
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Inbred BALB C
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • Pregnancy
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine-Arginine Splicing Factors
  • Tumor Cells, Cultured


  • Hyaluronan Receptors
  • RNA, Messenger
  • RNA-Binding Proteins
  • SRSF3 protein, human
  • Srsf3 protein, mouse
  • Serine-Arginine Splicing Factors