Heparanase Mechanisms in Brain-metastatic Breast Cancer
Abstract
Brain-metastatic breast cancer (BMBC) is common in patients expressing epidermal growth factor receptor1 or 2 (EGFR or HER2). Lapatinib is a small-molecule inhibitor of EGFR and HER2 and EGFR/HER2-associated downstream signaling which result in the suppression of brain colonization propensities of in vivo-selected MDA-MB-231BR variant (BR for brevity). Conversely, heparanase (HPSE) is a potent tumorigenic, angiogenic, and pro-metastatic enzyme known to initiate effects which drastically alter the metastatic outcome. We selected lapatinib-sensitive and lapatinib-resistant clones (BR-Ls and BR-Lr) from BR parental cells and demonstrated that HPSE over-expression in BR-Lr but not BR-Lr clones. Addition of HPSE to BR-Lr cells resulted in EGFR phosphorylation and signaling, and to an augmented HPSE secretion and activity. Second, we used SST0001, a non-anticoagulant heparinoid with a potent anti-HPSE activity, and examined its action on BR-Lr/Ls clones. SST0001 effectively synergized with lapatinib to inhibit cell proliferation of BR-Lr cells. Similarly, HPSE inhibition was associated with reduced EGFR phosphorylation levels in those tyrosine residues not targeted by lapatinib (Y992); and reflecting reduced pSRC, pAKT, and pERK levels. Lastly, SST0001 in combination with lapatinib blocked tumor growth in vivo and BMBC by BR-Lr cells. These results provide novel insights into mechanisms responsible for lapatinib resistance in BMBC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2013
- Accession Number
- ADA585985
Entities
People
- Dario Marchetti
Organizations
- Baylor College of Medicine