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PKC? Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance.

ABSTRACT: Breast cancer is the second leading cause of cancer mortality among women worldwide. The major problem with current treatments is tumor resistance, recurrence, and disease progression. ErbB-2-positive breast tumors are aggressive and frequently become resistant to trastuzumab or lapatinib. We showed previously that Notch-1 is required for trastuzumab resistance in ErbB-2-positive breast cancer.Here, we sought to elucidate mechanisms by which ErbB-2 attenuates Notch signaling and how this is reversed by trastuzumab or lapatinib.The current study elucidates a novel Notch inhibitory mechanism by which PKC? downstream of ErbB-2 (i) restricts the availability of Jagged-1 at the cell surface to transactivate Notch, (ii) restricts the critical interaction between Jagged-1 and Mindbomb-1, an E3 ligase that is required for Jagged-1 ubiquitinylation and subsequent Notch activation, (iii) reverses trastuzumab resistance in vivo, and (iv) predicts better outcome in women with ErbB-2-positive breast cancer.The clinical impact of these studies is PKC? is potentially a good prognostic marker for low Notch activity and increased trastuzumab sensitivity in ErbB-2-positive breast cancer. Moreover, women with ErbB-2-positive breast tumors expressing high Notch activation and low PKC? expression could be the best candidates for anti-Notch therapy.

SUBMITTER: Pandya K

PROVIDER: S-EPMC4703529 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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PKCα Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance.

Pandya Kinnari K Wyatt Debra D Gallagher Brian B Shah Deep D Baker Andrew A Bloodworth Jeffrey J Zlobin Andrei A Pannuti Antonio A Green Andrew A Ellis Ian O IO Filipovic Aleksandra A Sagert Jason J Rana Ajay A Albain Kathy S KS Miele Lucio L Denning Mitchell F MF Osipo Clodia C

Clinical cancer research : an official journal of the American Association for Cancer Research 20150908 1

<h4>Purpose</h4>Breast cancer is the second leading cause of cancer mortality among women worldwide. The major problem with current treatments is tumor resistance, recurrence, and disease progression. ErbB-2-positive breast tumors are aggressive and frequently become resistant to trastuzumab or lapatinib. We showed previously that Notch-1 is required for trastuzumab resistance in ErbB-2-positive breast cancer.<h4>Experimental design</h4>Here, we sought to elucidate mechanisms by which ErbB-2 att ...[more]

PMID: 26350262

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Project description:BackgroundTrastuzumab is a drug that targets the receptor tyrosine kinase HER2 and is essential for the treatment of HER2-positive breast cancer. Resistance to the drug leads to severe consequences, including disease recurrence, tumor enlargement, and metastasis. We hypothesized that trastuzumab treatment might be associated with phenotypic switching in HER2-positive breast cancer cells (BCCs), enabling them to escape and survive the effect of trastuzumab.MethodsWe conducted comprehensive immunophenotyping to detect phenotypic changes in HER2-positive BCCs treated with trastuzumab, based on criteria determined a priori. Based on immunophenotyping results, we characterized the vascular phenotypes of HER2-positive BCCs by western blotting, real-time RT-PCR, and tube formation assay. The vascular phenotype of tumor cells from clinical samples was evaluated by staining with periodic acid-Schiff and an anti-CD31 antibody. We explored small molecule inhibitors that suppress tube formation and determined the inhibitory mechanism.ResultsOut of 242 cell surface antigens, 9 antigens were significantly upregulated and 3 were significantly downregulated by trastuzumab treatment. All upregulated antigens were related to endothelial and stem cell phenotypes, suggesting that trastuzumab treatment might be correlated to switching to a vascular phenotype, namely, vasculogenic mimicry (VM). Several VM markers were upregulated in trastuzumab-treated cells, but these cells did not form tubes on Matrigel, a functional hallmark of VM. Upon analysis of three trastuzumab-resistant HER2-positive cell lines, we found that all three cell lines showed tube formation on Matrigel in the presence of angiogenic growth factors including EGF, FGF2, IGF1, or VEGF. Clinically, VM channels significantly increased in surviving cancer cell clusters of surgically removed tumors pretreated with trastuzumab and chemotherapy compared to both surgically removed tumors without prior systemic treatment and tumors biopsied before presurgical treatment with trastuzumab. Finally, we found that salinomycin completely suppressed VM in all three trastuzumab-resistant cell lines through disruption of actin cytoskeletal integrity.ConclusionsVM promotes metastasis and worsens patient outcomes. The present study indicates that HER2-positive BCCs can exhibit VM in an angiogenic microenvironment after eventually acquiring trastuzumab resistance. The clinical finding supports this in vitro observation. Thus, targeting VM might provide a therapeutic benefit to patients with HER2-positive breast cancer.

Dataset Information

PKC? Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance.

Publications

PKCα Attenuates Jagged-1-Mediated Notch Signaling in ErbB-2-Positive Breast Cancer to Reverse Trastuzumab Resistance.

Similar Datasets

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