p95HER2 and Breast Cancer

Arribas, Joaquı́n; Baselga, José; Pedersen, Kim; Parra-Palau, Josep Lluís

doi:10.1158/0008-5472.can-10-3795

Cited by 201 publications

(167 citation statements)

References 29 publications

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“…ErbB-2 is a major therapeutic target in breast cancer and the therapeutic agent used is an antibody to the ectodomain. Therefore the presence of these biologically active CTFs in tumor tissue represents a potential therapeutic problem (Arribas et al 2011). …”

Section: Nuclear Rtksmentioning

confidence: 99%

Receptor Tyrosine Kinases in the Nucleus

Carpenter

Liao

2013

Cold Spring Harbor Perspectives in Biology

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To date, 18 distinct receptor tyrosine kinases (RTKs) are reported to be trafficked from the cell surface to the nucleus in response to ligand binding or heterologous agonist exposure. In most cases, an intracellular domain (ICD) fragment of the receptor is generated at the cell surface and translocated to the nucleus, whereas for a few others the intact receptor is translocated to the nucleus. ICD fragments are generated by several mechanisms, including proteolysis, internal translation initiation, and messenger RNA (mRNA) splicing. The most prevalent mechanism is intramembrane cleavage by g-secretase. In some cases, more than one mechanism has been reported for the nuclear localization of a specific RTK. The generation and use of RTK ICD fragments to directly communicate with the nucleus and influence gene expression parallels the production of ICD fragments by a number of non-RTK cell-surface molecules that also influence cell proliferation. This review will be focused on the individual RTKs and to a lesser extent on other growth-related cell-surface transmembrane proteins.

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Section: Nuclear Rtksmentioning

confidence: 99%

Receptor Tyrosine Kinases in the Nucleus

Carpenter

Liao

2013

Cold Spring Harbor Perspectives in Biology

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“…EGFR and Erb-B2 activation may also be involved with resistance to radiotherapy, since both are upregulated/activated following exposure to ionising radiation. targeted therapies have been described, including subversion of trastuzumab binding to Erb-B2 by shed p95 ECD fragments (Ar- (Arribas et al, 2011); a switch to alternative signaling via other Erb-B family members (notably Erb-B3), alternative RTK such as c-MET, -ments (e.g. PI3 kinase-AKT-FOX1A) for example via loss of PTEN or by PIK3CA mutations.…”

Section: Links Between Erb-b Signalling and Resistance To Therapymentioning

confidence: 99%

The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology

Eccles¹

2011

Int. J. Dev. Biol.

159

123

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KEY WORDS: EGFR, c-Erb-B2, c-Erb-B3, c-Erb-B4, cancer The EGFR/ERB-B/HER familyThe epidermal growth factor receptor (EGFR) and its close relatives HER2/c-Erb-B2, Erb-B3 and Erb-B4 are type 1 transmembrane receptor tyrosine kinases (RTK) with key roles in embryonic development, tissue renewal/repair and cancer. A great deal has been learned about their structure, signalling pathways and aberrations linked to malignant transformation since the explosion of interest in this family in the 1980's. Early discoveriesregulated eyelid opening in mice, and as the binding partner for EGFR was found to have kinase activity when stimulated with ligands and to be capable of phosphorylating tyrosine residues on both itself and downstream targets. Even before EGFR was identiInt. J. Dev. Biol. 55: [685][686][687][688][689][690][691][692][693][694][695][696]

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“…Trastuzumab (Herceptin, Genentech, South San Francisco, CA, USA), a humanised MAB directed against the extracellular domain of HER2 (Carter et al 1992), has been shown to selectively exert anti-tumour effects in cancer models and patients with HER2-enriched breast cancer (Vogel et al 2002, Romond et al 2005. Despite the clinical effectiveness of trastuzumab in the treatment of HER2C tumours, intrinsic or secondary resistance to trastuzumab represents a significant hurdle (Arribas et al 2011), highlighting the importance of developing new therapies for this disease.…”

Section: Introductionmentioning

confidence: 99%

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

Lazaro¹,

Smith

Goddard

et al. 2013

Endocrine-Related Cancer

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The HER2 transmembrane receptor is a well-characterised predictive marker for trastuzumab benefit and may be associated with decreased benefit from endocrine therapy use. Despite the clinical effectiveness of anti-HER2 agents in such cases, resistance represents a significant limiting factor. Focal adhesion kinase (FAK) plays an important role in HER2 signalling, mediating downstream Akt activation in addition to HER2 cross talk with other growth factor receptors. In this study, we investigated the therapeutic potential of FAK in oestrogen receptor-positive (ERC)/HER2C breast cancer using the novel FAK-specific inhibitor PF4554878 ('PF878'). The activation of the FAK/HER2 signalling pathway was assessed in ERC/HER2K (MCF7 and T47D) and ERC/HER2C (BT-474 and MDAMB361) breast cancer cells in the presence or absence of PF878 and PF878Gtrastuzumab. The effects of PF878 on cell growth as a monotherapy and in combination with trastuzumab were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Coulter counting with isobologram analysis to determine synergy/additive effects. FAK activation (at Y861 but not at Y397) was highest in ERC/HER2C cells, which also demonstrated the greatest sensitivity to PF878. As a monotherapy, PF878 prevented heregulin-induced MDA361 cell migration, but had no significant effect on cell growth. The treatment of ERC/HER2C cells with PF878 and trastuzumab in combination resulted in the synergistic inhibition of cell proliferation. Underlying this was an abrogation of Akt activity and increased poly(ADP-ribose) polymerase cleavage, effects that were greatest in trastuzumab-refractory MDA361 cells. Collectively, these data support a role for FAK in ERC/HER2C breast cancer, where its targeting has the potential to improve trastuzumab response. This is particularly important in the context of ERC/HER2C, trastuzumab-refractory disease, where FAK inhibition may present an important strategy to restore trastuzumab sensitivity.

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p95HER2 and Breast Cancer

Cited by 201 publications

References 29 publications

Receptor Tyrosine Kinases in the Nucleus

Receptor Tyrosine Kinases in the Nucleus

The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

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