Protease Overexpression Facilitates Breast Cancer Spread

In breast cancer the loss of the tumor suppressor gene Lkb1 (liver kinase B1) causes overexpression of hepsin, a protease that degrades and disrupts the basement membrane (BM) structure that holds the tumor together.

Cancer researchers have sought to understand the mechanism that causes a highly structured tumor to break out of its site of initial growth and to spread to other tissues. In the current study investigators at the University of California, San Francisco (UCSF; USA) and the University of Helsinki (Finland) looked at the relationship between Lkb1, which is missing in about 25% of breast tumors, and hepsin, which is highly expressed in those tumors.

They reported in the January 20, 2012, online edition of the journal Proceedings of the [US] National Academy of Sciences that studies conducted on breast cancel mouse models and on breast cancer cell cultures had revealed that conditional deletion of Lkb1 in the mammary gland caused overexpression of the cell membrane protein hepsin. Increased hepsin activity resulted in compromised epithelial integrity. This was manifested by mislocalization of cell polarity markers, lateralization of tight junctions, deterioration of desmosomes and basement membrane (BM), and hyperbranching of the mammary ductal tree. Deactivation of hepsin allowed the basement membrane to recover.

These results showed that hepsin was a key factor mediating Lkb1 loss-induced structural alterations in mammary epithelium and BM fragmentation. Although loss of Lkb1 alone did not promote mammary tumorigenesis, the combination of Lkb1 deficiency and activation of the oncogene c-Myc led to dramatic acceleration in tumor formation.

“If we could delay or prevent a tumor from switching from one that grows in place to one that invades, then that would be a major milestone in cancer treatment,” said contributing author Dr. Zena Werb, professor of anatomy at UCSF. “We have observed that loss of Lkb1 combined with activation of a weak inducer of breast cancer – an oncogene such as Myc — can produce aggressive cancers. In humans, breast cancers that have diminished amounts of Lkb1 show strong hepsin expression. Since hepsin sits on the cell membrane, it should be accessible to drugs. We believe that hepsin forms a novel target for treatment of a subset of breast cancer patients.”

Related Links:
University of California, San Francisco
University of Helsinki