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Updated: Oct 3, 2025

The Use of Mouse Mammary Tumor Cells in an In Vitro Invasion Assay as a Measure of Oncogenic Cell Behavior
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Numb exon 9 inclusion regulates Integrinβ5 surface expression and promotes breast cancer metastasis

Yangjing Zhang1,2, Sascha E Dho2,3, Kamal Othman1,2

  • 1Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.

Oncogene
|February 19, 2022
PubMed

Insights

Numb protein splicing alterations promote cancer by increasing cell growth and metastasis. Removing exon 9-included Numb isoforms (Exon9in) reduces tumor progression and lung metastasis in mice.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Biology

Background:

  • The endocytic adaptor protein Numb typically suppresses tumors by downregulating oncogenic pathways.
  • Splicing alterations in Numb can lead to tumor-promoting activity, but the mechanisms are unclear.

Purpose of the Study:

  • To investigate the role of Numb exon 9 inclusion in cancer progression.
  • To elucidate the mechanisms by which Numb isoforms with exon 9 inclusion promote tumor growth and metastasis.

Main Methods:

  • Analysis of NUMB exon 9 inclusion in various cancer types, including breast cancer subtypes.
  • Experimental deletion of exon 9-included Numb isoforms (Exon9in) in breast cancer cells.
  • Quantitative proteome profiling to assess changes in protein expression and cellular functions.
  • Assessment of cell growth, lung metastasis in mouse models, and endocytic network remodeling.

Main Results:

  • Exon 9 inclusion in Numb isoforms (Exon9in) is prevalent in multiple cancers, including all breast cancer subtypes, and correlates with worse progression-free survival.
  • Deletion of Exon9in isoforms reduced breast cancer cell growth and prevented spontaneous lung metastasis in mice.
  • Loss of Exon9in led to downregulation of membrane receptors, adhesion molecules, extracellular matrix proteins, and epithelial-mesenchymal transition (EMT) markers.
  • Exon 9 deletion altered the endocytic network, decreased surface ITGβ5, and reduced cell spreading and downstream signaling.

Conclusions:

  • Exon9in isoform expression disrupts Numb's endocytic trafficking functions.
  • This disruption leads to increased surface expression of ITGβ5 and other plasma membrane proteins, promoting cell adhesion, EMT, and tumor metastasis.

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