Heparanase Mechanisms in Brain-metastatic Breast Cancer
Annual rept. 1 Apr 2012-31 Mar 2013
BAYLOR COLL OF MEDICINE HOUSTON TX
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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 EGFRHER2-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-LrLs 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.
- Anatomy and Physiology
- Medicine and Medical Research