Growth Factor Receptors in Breast Cancer: Potential for Therapeutic Intervention

Nahta, Rita; Hortobágyi, Gabriel N.; Esteva, Francisco J.

doi:10.1634/theoncologist.8-1-5

Cited by 102 publications

(75 citation statements)

References 119 publications

(112 reference statements)

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“…Alternatively, the neutralizing ability may be due to antibody 733 interfering with the interaction of heparanase with its substrate. Given the specificity of antibody reaction and the recent therapeutic use of antibodies in the clinic (Ludwig et al, 2003;Nahta et al, 2003), neutralizing anti-heparanase antibodies are extremely important reagents for basic heparanase research and, possibly, clinical applications. Raising monoclonal antibodies against the 14 amino acid sequence recognized by antibody 733 is hoped to yield an even better neutralizing ability and is currently in progress.…”

Section: Discussionmentioning

confidence: 99%

Processing and activation of latent heparanase occurs in lysosomes

Zetser¹,

Levy-Adam²,

Kaplan³

et al. 2004

Journal of Cell Science

207

259

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Heparanase is a heparan sulfate degrading endoglycosidase participating in extracellular matrix degradation and remodeling. Heparanase is synthesized as a 65 kDa non-active precursor that subsequently undergoes proteolytic cleavage, yielding 8 kDa and 50 kDa protein subunits that heterodimerize to form an active enzyme. The protease responsible for heparanase processing is currently unknown, as is the sub-cellular processing site. In this study, we characterize an antibody (733) that preferentially recognizes the active 50 kDa heparanase form as compared to the non-active 65 kDa heparanase precursor. We have utilized this and other anti-heparanase antibodies to study the cellular localization of the latent 65 kDa and active 50 kDa heparanase forms during uptake and processing of exogenously added heparanase. Interestingly, not only the processed 50 kDa, but also the 65 kDa heparanase precursor was localized to perinuclear vesicles, suggesting that heparanase processing occurs in lysosomes. Indeed, heparanase processing was completely inhibited by chloroquine and bafilomycin A1, inhibitors of lysosome proteases. Similarly, processing of membrane-targeted heparanase was also chloroquine-sensitive, further ruling out the plasma membrane as the heparanase processing site. Finally, we provide evidence that antibody 733 partially neutralizes the enzymatic activity of heparanase, suggesting that the N-terminal region of the molecule is involved in assuming an active conformation. Monoclonal antibodies directed to this region are likely to provide specific heparanase inhibitors and hence assist in resolving heparanase functions under normal and pathological conditions.

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Section: Discussionmentioning

confidence: 99%

Processing and activation of latent heparanase occurs in lysosomes

Zetser¹,

Levy-Adam²,

Kaplan³

et al. 2004

Journal of Cell Science

207

259

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“…Several novel tyrosine kinase inhibitors, such as the quinazolines, gefitinib, and erlotinib, function as competitive inhibitors at the tyrosine kinase ATP-binding site (32), while some are functional on RA synovial fibroblasts (33). Therapies directed against HER-2 and EGFR abound in breast, epithelial, ovarian, gut, and non-small-cell lung cancer (13,34,35). It has been reported that downstream signaling from phosphorylated tyrosine kinase domains of ErbB receptors uses different pathways for pro-versus antiangiogenic factors, a critical feature in modulation of the homeostatic balance of physiologic versus pathologic angiogenesis (36).…”

Section: Discussionmentioning

confidence: 99%

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

Sumariwalla¹,

Pei²,

Zhang³

et al. 2008

Arthritis & Rheumatism

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Objective. To evaluate the therapeutic potential of the human epidermal growth factor receptor (HER) family inhibitor, herstatin, in an animal model of arthritis.Methods. Constructs of herstatin and modified tissue plasminogen activator (tPA)-herstatin were expressed in HEK 293T cells, and secreted protein was analyzed by Western blotting. Tissue PA-herstatin adenovirus (Ad-tPA-Her) was prepared, and titers established. Gene expression of Ad-tPA-Her was determined by polymerase chain reaction using HeLa cells. Pharmacokinetics of gene and protein expression in vivo in liver tissue and serum samples were confirmed via intravenous administration of Ad-tPA-Her. Clinical signs of disease were monitored in arthritic DBA/1 mice after therapeutic administration of Ad-tPA-Her, and histologic analysis of hind foot specimens was performed.Results. Native herstatin was not secreted in supernatants, while modified tPA-herstatin was detected in abundance. HeLa cells stably expressed the tPA-herstatin gene when infected with virus. Additionally, tPA-herstatin gene and protein expression was observed over time in mice treated with virus. Importantly, Ad-tPA-Her, when administered therapeutically to arthritic mice, controlled clinical and histologic signs of disease and reduced the number of joints with severe damage.Conclusion. Our results support the notion that the human epidermal growth factor receptor family has a role in the progression of collagen-induced arthritis. The novel tPA-herstatin fusion protein could be used as an effective therapeutic tool for control of inflammatory disorders involving an angiogenic component.

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“…20), and Ras family proteins (21,22) are mutated, amplified, or hyperactivated in many human cancers. Furthermore, in several epithelial cell models, including the murine mammary epithelial cell line EpH4, metastatic potential requires the cooperation of TGF-b signaling with hyperactive ERK/MAPK signaling, caused by oncogenic RTKs (e.g., HER2), Ras, or Raf (23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%