Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer
Heparanase (HPSE) is the dominant mammalian endoglycosidase and important tumorigenic, angiogenic, and pro-metastatic molecule. Highest levels of HPSE activity have been consistently detected in cells possessing highest propensities to colonize the brain, emphasizing the therapeutic potential for ta...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-01-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558614001882 |
| _version_ | 1818394671318040576 |
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| author | Lixin Zhang Jason A. Ngo Michael D. Wetzel Dario Marchetti |
| author_facet | Lixin Zhang Jason A. Ngo Michael D. Wetzel Dario Marchetti |
| author_sort | Lixin Zhang |
| collection | DOAJ |
| description | Heparanase (HPSE) is the dominant mammalian endoglycosidase and important tumorigenic, angiogenic, and pro-metastatic molecule. Highest levels of HPSE activity have been consistently detected in cells possessing highest propensities to colonize the brain, emphasizing the therapeutic potential for targeting HPSE in brain metastatic breast cancer (BMBC). Lapatinib (Tykerb) is a small-molecule and dual inhibitor of human epidermal growth factor receptor1 and 2 (EGFR and HER2, respectively) which are both high-risk predictors of BMBC. It was approved by the US Food and Drug Administration for treatment of patients with advanced or metastatic breast cancer. However, its role is limited in BMBC whose response rates to lapatinib are significantly lower than those for extracranial metastasis. Because HPSE can affect EGFR phosphorylation, we examined Roneparstat, a non-anticoagulant heparin with potent anti-HPSE activity, to inhibit EGFR signaling pathways and BMBC onset using lapatinib-resistant clones generated from HER2-transfected, EGFR-expressing MDA-MB-231BR cells. Cell growth, EGFR pathways, and HPSE targets were assessed among selected clones in the absence or presence of Roneparstat and/or lapatinib. Roneparstat overcame lapatinib resistance by inhibiting pathways associated with EGFR tyrosine residues that are not targeted by lapatinib. Roneparstat inhibited the growth and BMBC abilities of lapatinib-resistant clones. A molecular mechanism was identified by which HPSE mediates an alternative survival pathway in lapatinib-resistant clones and is modulated by Roneparstat. These results demonstrate that the inhibition of HPSE-mediated signaling plays important roles in lapatinib resistance, and provide mechanistic insights to validate the use of Roneparstat for novel BMBC therapeutic strategies. |
| first_indexed | 2024-12-14T06:04:55Z |
| format | Article |
| id | doaj.art-a3be0fc4425f482288fbd2b407753fa4 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-14T06:04:55Z |
| publishDate | 2015-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-a3be0fc4425f482288fbd2b407753fa42022-12-21T23:14:20ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022015-01-0117110111310.1016/j.neo.2014.11.007Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancerLixin Zhang0Jason A. Ngo1Michael D. Wetzel2Dario Marchetti3Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030Department of Pathology & Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030Heparanase (HPSE) is the dominant mammalian endoglycosidase and important tumorigenic, angiogenic, and pro-metastatic molecule. Highest levels of HPSE activity have been consistently detected in cells possessing highest propensities to colonize the brain, emphasizing the therapeutic potential for targeting HPSE in brain metastatic breast cancer (BMBC). Lapatinib (Tykerb) is a small-molecule and dual inhibitor of human epidermal growth factor receptor1 and 2 (EGFR and HER2, respectively) which are both high-risk predictors of BMBC. It was approved by the US Food and Drug Administration for treatment of patients with advanced or metastatic breast cancer. However, its role is limited in BMBC whose response rates to lapatinib are significantly lower than those for extracranial metastasis. Because HPSE can affect EGFR phosphorylation, we examined Roneparstat, a non-anticoagulant heparin with potent anti-HPSE activity, to inhibit EGFR signaling pathways and BMBC onset using lapatinib-resistant clones generated from HER2-transfected, EGFR-expressing MDA-MB-231BR cells. Cell growth, EGFR pathways, and HPSE targets were assessed among selected clones in the absence or presence of Roneparstat and/or lapatinib. Roneparstat overcame lapatinib resistance by inhibiting pathways associated with EGFR tyrosine residues that are not targeted by lapatinib. Roneparstat inhibited the growth and BMBC abilities of lapatinib-resistant clones. A molecular mechanism was identified by which HPSE mediates an alternative survival pathway in lapatinib-resistant clones and is modulated by Roneparstat. These results demonstrate that the inhibition of HPSE-mediated signaling plays important roles in lapatinib resistance, and provide mechanistic insights to validate the use of Roneparstat for novel BMBC therapeutic strategies.http://www.sciencedirect.com/science/article/pii/S1476558614001882 |
| spellingShingle | Lixin Zhang Jason A. Ngo Michael D. Wetzel Dario Marchetti Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer Neoplasia: An International Journal for Oncology Research |
| title | Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer |
| title_full | Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer |
| title_fullStr | Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer |
| title_full_unstemmed | Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer |
| title_short | Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer |
| title_sort | heparanase mediates a novel mechanism in lapatinib resistant brain metastatic breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1476558614001882 |
| work_keys_str_mv | AT lixinzhang heparanasemediatesanovelmechanisminlapatinibresistantbrainmetastaticbreastcancer AT jasonango heparanasemediatesanovelmechanisminlapatinibresistantbrainmetastaticbreastcancer AT michaeldwetzel heparanasemediatesanovelmechanisminlapatinibresistantbrainmetastaticbreastcancer AT dariomarchetti heparanasemediatesanovelmechanisminlapatinibresistantbrainmetastaticbreastcancer |