Multiple molecular mechanisms underlying trastuzumab and lapatinib resistance in JIMT-1 breast cancer cells

Köninki, Katri; Barok, Márk; Tanner, Minna; Staff, Synnöve; Pitkänen, Jukka; Hemmilä, Päivikki; Ilvesaro, Joanna; Isola, Jorma

doi:10.1016/j.canlet.2010.02.002

Cited by 95 publications

(84 citation statements)

References 43 publications

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“…We and others have demonstrated that the growthinhibitory effects of HER inhibitors indeed correlate with expression levels of certain HER ligands (29,30). JIMT-1 breast cancer cells not only exhibit primary resistance to trastuzumab but demonstrate further cross-resistance to several HER2-inhibiting drugs including the HERdimerization inhibitor antibody pertuzumab (2C4) and the small molecule HER TKIs CI1033 (canertinib), ZD1839 (gefitinib) and lapatinib (11,33). It is noteworthy that, when compared to HER2 + SKBR3 cells, a luminal breast cancer model exquisitely sensitive to HER targeting agents including trastuzumab, gefitinib and lapatinib, the JIMT-1 secretome accumulated significantly higher amounts of several growth factors such as amphiregulin and EGF (two high-affinity ligands of EGFR (HER1), a growth factor receptor commonly found overexpressed in basal-like breast tumors) as well as several isoforms of the pro-angiogenic factors TGFß and VEGF.…”

Section: Discussionmentioning

confidence: 99%

Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

et al. 2010

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Abstract.Pioneering clinical studies in de novo refractoriness to the anti-HER2 monoclonal antibody trastuzumab have suggested that HER2 gene-amplification can take place also in a basal-like molecular background to generate basal/HER2 + tumors intrinsically resistant to trastuzumab. Here, we first investigated the unique histogenesis of the basal/HER2 + phenotype in breast carcinomas. The presence of basal CK5/CK6 cytokeratin expression in HER2 + tumors revealed a significant overlap in the histological features of HER2 + /CK5/6 + and basal-like breast carcinomas. Basal/ HER2 + tumors were typically poorly differentiated, highgrade invasive ductal carcinomas with large geographic necrosis, pushing margins of invasion, syncytial arrangement of tumor cells, ribbon-or festoon-like architecture, squamous metaplasia, stromal lymphocytic infiltrates, high mitotic index and strong p53 positivity. Secondly, we performed low-scale proteomic approaches in JIMT-1 cells, a unique model of HER2-gene amplified trastuzumab-resistant breast carcinoma with a basal-like phenotype, to develop biomarker signatures that may differentiate trastuzumab-responsive from non-responsive tumors. When applying antibody-based array technology to the extracellular milieu of trastuzumabrefractory JIMT-1 and trastuzumab-sensitive SKBR3 cell cultures, JIMT-1 cells were found to secrete higher amounts of several growth factors including amphiregulin, EGF, IGFBP-6, PDGF-AA, neurotrophins, TGFß and VEGF. Semiquantitative signaling node multi-target sandwich ELISAs revealed that JIMT-1 cells drastically overactivate RelA, the prosurvival subunit of NF-κB as compared to trastuzumabsensitive luminal/HER2 + SKBR3 cells. When simultaneously assessing the activation status of 42 receptor tyrosine kinases (RTK) using a human phospho-RTK array, JIMT-1 cells were found to constitutively display hyperactivation of the insulin-like growth factor-I receptor (IGF-1R). High-content immunofluorescence imaging revealed that activated IGF-1R mainly localized at focal adhesion-like structures in JIMT-1 cells. In vitro wound healing assays suggested that this functional reorganization of the JIMT-1 cytoskeletal reorganization may account for an exacerbated trastuzumab-refractory 'migratogenic' phenotype. Forthcoming studies should validate the notion that identification of basal-like immunophenotypes and/or basal-like molecular signatures within HER2 + breast carcinomas may provide rapid means to define subgroups of breast cancer patients likely to display resistance to trastuzumab ab initio.

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Section: Discussionmentioning

confidence: 99%

Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

et al. 2010

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“…JIMT-1 human breast cancer cells 67 were purchased from DSMZ (Germany) and were grown in regular Dulbecco's modified Eagle's medium (DMEM). These cells express high levels of the IGF-1R protein.…”

Section: Cell Lines and Inhibitorsmentioning

confidence: 99%

IGF-1R peptide vaccines/mimics inhibit the growth of BxPC3 and JIMT-1 cancer cells and exhibit synergistic antitumor effects with HER-1 and HER-2 peptides

et al. 2014

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“…In this regard, intrinsic trastuzumab resistance in a cell line isolated from the pleural fluid of a HER2-positive breast cancer patient with progressive disease on trastuzumab (i.e., JIMT-1) constitutes an excellent scenario to discover alternative explanations for de novo resistance to trastuzumab (13,14). First, high-resolution genomic profiles have confirmed that, among intrinsic breast cancer molecular subtypes (15,16), trastuzumab-sensitive BT-474 and SKbR3 breast cancer cell lines (two in vitro models widely used as HER2-gene amplified trastuzumab-sensitive breast carcinomas) display a luminal b-like gene expression phenotype whereas trastuzumab-refractory JIMT-1 cells rather exhibit the closest resemblance to the actual HER2-positive gene expression breast cancer subtype (17). Second, JIMT-1 cells provide a valuable experimental model for the studies of resistance to HER-targeted therapies as they are largely insensitive to the growth inhibitory effects of the HER2/HER3 monoclonal antibodies trastuzumab and pertuzumab and to the HER1/HER2 tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and lapatinib (13,14,17).…”

Section: Introductionmentioning

confidence: 96%

“…First, high-resolution genomic profiles have confirmed that, among intrinsic breast cancer molecular subtypes (15,16), trastuzumab-sensitive BT-474 and SKbR3 breast cancer cell lines (two in vitro models widely used as HER2-gene amplified trastuzumab-sensitive breast carcinomas) display a luminal b-like gene expression phenotype whereas trastuzumab-refractory JIMT-1 cells rather exhibit the closest resemblance to the actual HER2-positive gene expression breast cancer subtype (17). Second, JIMT-1 cells provide a valuable experimental model for the studies of resistance to HER-targeted therapies as they are largely insensitive to the growth inhibitory effects of the HER2/HER3 monoclonal antibodies trastuzumab and pertuzumab and to the HER1/HER2 tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and lapatinib (13,14,17). Owing to redundant molecular mechanisms such as low levels of HER2 protein expression and activation despite HER2 gene amplification, loss of the phosphatase and tensin homolog (PTEN) tumor suppressor, activating mutation of the PIK3CA gene, and intrinsic enrichment in the CD44 pos CD24 neg/low phenotype with stem/progenitor cell properties (17,18), JIMT-1 cell line constitutes a naturallyoccurring 'extreme phenotype' of de novo cross-refractoriness to multiple HER targeting therapies.…”

Section: Introductionmentioning

confidence: 96%

Crude phenolic extracts from extra virgin olive oil circumvent de novo breast cancer resistance to HER1/HER2-targeting drugs by inducing GADD45-sensed cellular stress, G2/M arrest and hyperacetylation of Histone H3

Menéndez¹

2011

Int J Oncol

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Abstract.Characterization of the molecular function of complex phenols naturally present in extra virgin olive oil (EVOO) against the HER2-gene amplified JIMT-1 cell line, a unique breast cancer model that inherently exhibits cross-resistance to multiple HER1/2-targeted drugs including trastuzumab, gefitinib, erlotinib and lapatinib, may underscore innovative cancer molecules with novel therapeutic targets because they should efficiently circumvent de novo resistance to HER1/2 inhibitors in order to elicit tumoricidal effects. We identified pivotal signaling pathways associated with the efficacy of crude phenolic extracts (PEs) obtained from 14 monovarietals of Spanish EVOOs. i) MTT-based cell viability and HPLC coupled to time-of-flight (TOF) mass spectrometry assays revealed that anti-cancer activity of EVOO PEs positively correlated with the phenolic index (i.e., total content of phenolics) and with a higher presence of the complex polyphenols secoiridoids instead of lignans. ii) Genome-wide analyses using 44 K Agilent's whole human arrays followed by Gene Set Enrichment Analysis (GSEA)-based screening of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database revealed a differential modulation of the JIMT-1 transcriptome at the level of the cell cycle and p53 pathways. EVOO PEs differentially impacted the expression status of stress-sensing, G2-M checkpoint-related GADD45 genes and of p53-related CDKN1A, CDKN1C and PMAIP-1 genes. iii) Cell cycle and fluorescence microscopy analyses confirmed that secoiridoid-rich EVOO PE inhibited mitosis to promote G2-M cell cycle arrest. This was accompanied with the appearance of diffuse, even DNA staining with γH2AX and pan-nuclear hyperacetylation of Histone H3 at Lysine 18. iv) Semi-quantitative Signaling Node Multi-Target ELISAs determined that secoiridoid-rich EVOO PE drastically activated the mitogen-activated protein kinases MEK1 and p38 MAPK, a GADD45-related kinase involved in Histone H3 acetylation. Secoiridoids, a family of complex polyphenols characteristic of Oleaceae plants, appear to permit histones to remain in hyperacetylated states and through the resulting alterations in gene regulation to reduce mitotic viability and metabolic competence of breast cancer cells inherently refractory to HER-targeting therapies ab initio. Oleaceae secoiridoids could provide a valuable phytochemical platform for the design of more pharmacologically active secondgeneration phytopharmaceutical anti-breast cancer molecules with a unique mode of action.

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Multiple molecular mechanisms underlying trastuzumab and lapatinib resistance in JIMT-1 breast cancer cells

Cited by 95 publications

References 43 publications

Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

Pathway-focused proteomic signatures in HER2-overexpressing breast cancer with a basal-like phenotype: New insights into de novo resistance to trastuzumab (Herceptin)

IGF-1R peptide vaccines/mimics inhibit the growth of BxPC3 and JIMT-1 cancer cells and exhibit synergistic antitumor effects with HER-1 and HER-2 peptides

Crude phenolic extracts from extra virgin olive oil circumvent de novo breast cancer resistance to HER1/HER2-targeting drugs by inducing GADD45-sensed cellular stress, G2/M arrest and hyperacetylation of Histone H3

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