Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

Boone, J.; Bhosle, Jaishree; Tilby, M.J.; Hartley, John A.; Hochhauser, Daniel

doi:10.1158/1535-7163.mct-09-0219

Cited by 52 publications

(30 citation statements)

References 42 publications

(57 reference statements)

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“…Notably, relatively high concentrations of CDDP and DOX were used in the present study; however, this is similar to previous studies, of which several also used longer treatment durations (22,25,(29)(30)(31)(32)(33)(34). Data from a previous study (11), in addition to titration data from the present study, provided the optimum conditions for the phosphorylation of ERK in addition to ErbB2/3.…”

Section: Discussionsupporting

confidence: 81%

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

et al. 2017

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Abstract. Cisplatin (CDDP) and doxorubicin (DOX) are chemotherapeutic drugs that trigger apoptosis by inducing DNA-damage. A previous study using breast cancer cells demonstrated the negative feedback modulation of the epidermal growth factor receptor (EGFR) and receptor tyrosine-protein kinase erbB-2 (ErbB2) via extracellular signal-regulated kinase (ERK)-mediated phosphorylation of conserved Thr-669 and Thr-677 residues, respectively, in the juxtamembrane domain. In addition, CDDP has been identified to cause negative feedback inhibition of activated EGFR in lung cancer cells. In the present study, the role of phosphorylation in the feedback control of the ErbB2/ErbB3 heterodimer in human breast and gastric cancer cells was investigated. Phosphorylation of ErbB2 at Thr-677 was induced by CDDP and DOX, which in turn reduced tyrosine autophosphorylation of ErbB2 and ErbB3. Treatment with trametinib, a mitogen-activated protein kinase inhibitor that blocks ERK-mediated Thr-677 phosphorylation, and substitution of Thr-677 to alanine, blocked the feedback inhibition of ErbB2 and ErbB3. In addition, these agents caused the degradation of ErbB proteins through the activation of p38 mitogen-activated protein kinase (p38) and ERK. These results demonstrate that chemotherapeutic agents trigger ERK-and p38-mediated post-translational downregulation of ErbB receptors. IntroductionThe receptor tyrosine-protein kinase erbB (ErbB) family of receptor tyrosine kinases (RTKs) consists of four members, ErbB1 [also known as epidermal growth factor receptor (EGFR)/HER1], ErbB2 (also known as proto-oncogene Neu/HER2), ErbB3 (also termed HER3) and ErbB4 (also termed HER4) (1). Upon activation, ErbB family members form homodimers or heterodimers that serve important roles in biological processes associated with differentiation, proliferation and apoptosis, primarily through mitogen-activated protein kinase and the phosphoinositide-3 kinase/RAC-alpha serine/threonine-protein kinase signaling pathways (2-6). ErbB mutations are frequently identified in human cancer, leading to aberrant ErbB expression and subsequent survival signals (7). Therefore, drugs targeting the ErbB receptors have been a central focus of cancer research (8,9).RTKs are non-canonically regulated by phosphorylation at their serine and threonine residues. For example, extracellular signal-regulated kinase (ERK)-mediated phosphorylation of a conserved threonine in the juxtamembrane domain of EGFR (Thr-669) and ErbB2 (Thr-677) is a typical negative feedback mechanism of ErbB dimers (10,11). Tumor necrosis factor-α-induced and p38 mitogen-activated protein kinase (p38)-mediated phosphorylation of EGFR (Ser-1046/1047) at the C-terminal tail is associated endocytosis of the receptor. A previous study demonstrated that cisplatin (CDDP), a well known DNA-damaging agent, induces the non-canonical phosphorylation of EGFR proteins harboring an activating mutation in lung cancer cells, resulting in negative feedback inhibition and endocytosis (12).ErbB2, which has been demonstr...

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Section: Discussionsupporting

confidence: 81%

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

et al. 2017

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“…It is overexpressed in about 30% of breast cancer patients, which leads to poor clinical outcomes [2-7]. HER2 is a mitogenic tyrosine kinase receptor, known to induce transforming signals and hence directly promotes cell proliferation [8]. The HER2 expression can lead to impaired DNA repair [8], angiogenesis [9] and metastasis [10].…”

Section: Introductionmentioning

confidence: 99%

“…HER2 is a mitogenic tyrosine kinase receptor, known to induce transforming signals and hence directly promotes cell proliferation [8]. The HER2 expression can lead to impaired DNA repair [8], angiogenesis [9] and metastasis [10]. Furthermore, HER2 has been shown to interact with several other growth promoting mechanisms like TGFβ, estrogen receptor, FOXO1A, Src kinases, ILK and integrins to reinforce oncogenesis and metastasis [11-16].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HER2-integrin signaling by Cucurbitacin B leads to in vitro and in vivo breast tumor growth suppression

Gupta

Srivastava

2014

Oncotarget

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HER2, an oncogenic receptor is overexpressed in about 25-30% of breast cancer patients. HER2 has been shown to play role in tumor promotion by having cross-talk with multiple oncogenic pathways in cancer cells. Our results show that Cucurbitacin B (CuB), a triterpenoid steroidal compound inhibited the growth of various breast cancer cells with an IC50 ranging from 18-50nM after 48 and 72 h of treatment. Our study also revealed the significant inhibitory effects of CuB on HER2 and integrin signaling in breast cancer. Notably, CuB inhibited ITGA6 and ITGB4 (integrin α6 & integrin β4), which are overexpressed in breast cancer. Furthermore, CuB also induced the expression of major ITGB1and ITGB3, which are known to cause integrin-mediated cell death. In addition, we observed that TGFβ treatment resulted in the increased association of HER2 with ITGA6 and this association was inhibited by CuB treatment. Efficacy of CuB was tested in vivo using two different orthotopic models of breast cancer. MDA-MB-231 and 4T-1 cells were injected orthotopically in the mammary fat pad of female athymic nude mice or BALB/c mice respectively. Our results showed that CuB administration inhibited MDA-MB-231 orthotopic tumors by 55%, and 4T-1 tumors by 40%. The 4T-1 cells represent stage IV breast cancer and form very aggressive tumors. CuB mediated breast tumor growth suppression was associated with the inhibition of HER2/integrin signaling. Our results suggest novel targets of CuB in breast cancer in vitro and in vivo.

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“…[45][46][47] In part these findings correlate with the recognized additive and synergistic levels of cytotoxic anti-neoplastic potency of anti-HER2/neu (inhibited HER2/neu function) in concert with conventional chemotherapeutics such as cyclophosphamide, 48,49 docetaxel, 48 doxorubicin, 48,49 etoposide, 48 methotrexate, 48 paclitaxel, 48,49 or vinblastine. 48 Similar to anti-HER2/ neu, [48][49][50][51][52][53] other trophic receptor inhibitors including anti-EGFR [54][55][56] and anti-VEGFR 57-59 also create additive and synergistic levels of cytotoxic anti-neoplastic potency when applied in combination with conventional chemotherapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

Coyne

Jones²,

Bear³

2012

Cancer Biotherapy and Radiopharmaceuticals

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The C 3 -monoamine on the carbohydrate moiety (daunosamine -NH 2 -3¢) of epirubicin was reacted under anhydrous conditions with succinimidyl 4,4-azipentanoate to create a covalent UV-photoactivated epirubicin-(C 3 -amide) intermediate with primary amine-reactive properties. A synthetic covalent bond between the UV-photoactivated epirubicin-(C 3 -amide) intermediate and the e-amine of lysine residues within the amino acid sequence of anti-HER2/neu monoclonal immunoglobulin was subsequently created by exposure to UV light (354 nm) for 15 minutes. Size-separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis combined with immunodetection analysis and chemiluminescent autoradiographic imaging revealed a lack of IgG-IgG polymerization or degradative protein fragmentation of the covalent epirubicin-(C 3 -amide)-[anti-HER2/neu] immunochemotherapeutic. Retained binding-avidity of epirubicin-(C 3 -amide)-[anti-HER2/neu] was validated by cell-ELISA utilizing monolayer populations of chemotherapeutic-resistant mammary adenocarcinoma SKBr-3 which highly overexpress membrane-associated HER2/neu complexes. Between epirubicin-equivalent concentrations of 10 -10 to 10 -6 M the covalent epirubicin-(C 3 -amide)-[anti-HER2/neu] immunochemotherapeutic consistently evoked levels of cytotoxic anti-neoplastic potency that were highly analogous to chemotherapeuticequivalent concentrations of epirubicin. Cytotoxic anti-neoplastic potency of epirubicin-(C 3 -amide)-[anti-HER2/ neu] against chemotherapeutic-resistant mammary adenocarcinoma SKBr-3 challenged with epirubicin-(C 3 -amide)-[anti-HER2/neu] at an epirubicin-equivalent concentration of 10 -6 M was 88.5% (e.g., 11.5% residual survival). Between final epirubicin-equivalent concentrations of 10 -8 and 10 -7 M there was a marked threshold increase in the mean cytotoxic anti-neoplastic activity for epirubicin-(C 3 -amide)-[anti-HER2/neu] from 9.9% to 66.9% (90.2% to 33.1% residual survival).

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Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

Cited by 52 publications

References 42 publications

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

Inhibition of HER2-integrin signaling by Cucurbitacin B leads to in vitro and in vivo breast tumor growth suppression

Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

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Involvement of the HER2 pathway in repair of DNA damage produced by chemotherapeutic agents

Cited by 52 publications

References 42 publications

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

Mechanisms for DNA‑damaging agent‑induced inactivation of ErbB2 and ErbB3 via the ERK and p38 signaling pathways

Inhibition of HER2-integrin signaling by Cucurbitacin B leads to in vitro and in vivo breast tumor growth suppression

Synthesis of a Covalent Epirubicin-(C3-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate

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Synthesis of a Covalent Epirubicin-(C₃-amide)-Anti-HER2/neuImmunochemotherapeutic Utilizing a UV-Photoactivated Anthracycline Intermediate