Cytogenetic characterization and gene expression profiling of the trastuzumab-resistant breast cancer cell line JIMT-1

Rennstam, Karin; Jönsson, Göran; Tanner, Minna; Bendahl, Pär‐Ola; Staaf, Johan; Karhu, Ritva; Baldetorp, Bo; Borg, Åke; Isola, Jorma

doi:10.1016/j.cancergencyto.2006.09.014

Cited by 20 publications

(14 citation statements)

References 25 publications

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“…While limited data exist about the role of CDK4-cyclin D 1 interactions and trastuzumab resistance, these data suggest a role for dual targeting of the HER2 pathway and CDK4/6. Molecular profiling of the JIMT-1 human breast cancer cell line derived from a woman with progressive HER2-amplified disease while receiving trastuzumab did identify a small amplicon on 12q14.1, which contains the CDK4 gene [48]. …”

Section: Discussionmentioning

confidence: 99%

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro

et al. 2009

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IntroductionAlterations in cell cycle regulators have been implicated in human malignancies including breast cancer. PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases (CDK)4 and CDK6 with ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. To identify predictors of response, we determined the in vitro sensitivity to PD 0332991 across a panel of molecularly characterized human breast cancer cell lines.MethodsForty-seven human breast cancer and immortalized cell lines representing the known molecular subgroups of breast cancer were treated with PD 0332991 to determine IC50 values. These data were analyzed against baseline gene expression data to identify genes associated with PD 0332991 response.ResultsCell lines representing luminal estrogen receptor-positive (ER+) subtype (including those that are HER2 amplified) were most sensitive to growth inhibition by PD 0332991 while nonluminal/basal subtypes were most resistant. Analysis of variance identified 450 differentially expressed genes between sensitive and resistant cells. pRb and cyclin D1 were elevated and CDKN2A (p16) was decreased in the most sensitive lines. Cell cycle analysis showed G0/G1 arrest in sensitive cell lines and Western blot analysis demonstrated that Rb phosphorylation is blocked in sensitive lines but not resistant lines. PD 0332991 was synergistic with tamoxifen and trastuzumab in ER+ and HER2-amplified cell lines, respectively. PD 0332991 enhanced sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade.ConclusionsThese studies suggest a role for CDK4/6 inhibition in some breast cancers and identify criteria for patient selection in clinical studies of PD 0332991.

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Section: Discussionmentioning

confidence: 99%

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro

et al. 2009

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“…One reported mechanism of trastuzumab resistance in the JIMT-1 cells is the up-regulation of MUC-4 that can result in steric hindrance, thereby physically blocking the binding of trastuzumab to HER2 (22,23). Another interesting study reported that p53 is up-regulated in JIMT-1 cells; although this may provide a mechanism of resistance to trastuzumab, the p53 mutation status was not evaluated (24). Characterization of the p53 mutational status may provide clues to the IPI-504 mechanism of action in JIMT-1 because mutant p53 is a reported Hsp90 client protein (reviewed in refs.…”

Section: Discussionmentioning

confidence: 99%

Antitumor efficacy of IPI-504, a selective heat shock protein 90 inhibitor against human epidermal growth factor receptor 2–positive human xenograft models as a single agent and in combination with trastuzumab or lapatinib

Leow¹,

Chesebrough²,

Coffman³

et al. 2009

Molecular Cancer Therapeutics

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IPI-504 is a novel, highly soluble small-molecule inhibitor of heat shock protein 90 (Hsp90), a protein chaperone essential for regulating homeostasis of oncoproteins and cell signaling proteins. Human epidermal growth factor receptor 2 (HER2; ErbB2) oncoprotein, expressed in a subset of metastatic breast cancers, is a Hsp90 client protein. In this study, we investigated the antitumor activity and the mechanism of action of IPI-504 in HER2 + , trastuzumabsensitive and trastuzumab-refractory cell lines in vitro and in vivo. IPI-504 exhibited potent antiproliferative activities (range of IC 50 , 10-40 nmol/L) against several tumor cell lines examined, whereby mechanism of action was mediated through HER2 and Akt degradation. Both intravenous and oral administration of IPI-504 assessed in multiple schedules showed potent tumor growth inhibition in vivo with corresponding degradation of HER2. The tolerability and efficacy of IPI-504 combined with either trastuzumab or lapatinib were also investigated in HER2 + tumor xenograft models. Combination of IPI-504 with trastuzumab significantly enhanced tumor growth delay and induced greater responses when compared with either agent alone. Although, as expected, trastuzumab alone did not exhibit any significant antitumor activity in the trastuzumab-resistant JIMT-1 model, IPI-504 administered in combination with trastuzumab yielded greater antitumor efficacy than either agent alone. Finally, combination of IPI-504 and lapatinib was well tolerated up to 50 mg/kg IPI-504 and 100 mg/kg lapatinib and resulted in significant delay in tumor growth, including partial and complete tumor responses. These lines of evidence support the development of IPI-504 in HER2-positive breast cancers as a single agent and in combination with either trastuzumab or lapatinib.

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“…Basal BC cell line JIMT-1 cells are HER2+, trastuzumab-refractory, ER−, and Vimentin+. The de novo resistance of JIMT-1 cell to trastuzumab can be explained by the emergence of trastuzumab-resistance BCSCs due to the dynamic interaction between HER2 and EMT [98,99,100,101,102,103,104]. JIMT-1 cell line is composed of approximately 10% CD44+/CD24− BCSC.…”

Section: Emt Drives Resistance To Trastuzumabmentioning

confidence: 99%

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

Nami

Wang

2017

Cancers

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HER2 receptor tyrosine kinase that is overexpressed in approximately 20% of all breast cancers (BCs) is a poor prognosis factor and a precious target for BC therapy. Trastuzumab is approved by FDA to specifically target HER2 for treating HER2+ BC. However, about 60% of patients with HER2+ breast tumor develop de novo resistance to trastuzumab, partially due to the loss of expression of HER2 extracellular domain on their tumor cells. This is due to shedding/cleavage of HER2 by metalloproteinases (ADAMs and MMPs). HER2 shedding results in the accumulation of intracellular carboxyl-terminal HER2 (p95HER2), which is a common phenomenon in trastuzumab-resistant tumors and is suggested as a predictive marker for trastuzumab resistance. Up-regulation of the metalloproteinases is a poor prognosis factor and is commonly seen in mesenchymal-like cancer stem cells that are risen during epithelial to mesenchymal transition (EMT) of tumor cells. HER2 cleavage during EMT can explain why secondary metastatic tumors with high percentage of mesenchymal-like cancer stem cells are mostly resistant to trastuzumab but still sensitive to lapatinib. Importantly, many studies report HER2 interaction with oncogenic/stemness signaling pathways including TGF-β/Smad, Wnt/β-catenin, Notch, JAK/STAT and Hedgehog. HER2 overexpression promotes EMT and the emergence of cancer stem cell properties in BC. Increased expression and activation of metalloproteinases during EMT leads to proteolytic cleavage and shedding of HER2 receptor, which downregulates HER2 extracellular domain and eventually increases trastuzumab resistance. Here, we review the hypothesis that a negative feedback loop between HER2 and stemness signaling drives resistance of BC to trastuzumab.

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Cytogenetic characterization and gene expression profiling of the trastuzumab-resistant breast cancer cell line JIMT-1

Cited by 20 publications

References 25 publications

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro

PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro

Antitumor efficacy of IPI-504, a selective heat shock protein 90 inhibitor against human epidermal growth factor receptor 2–positive human xenograft models as a single agent and in combination with trastuzumab or lapatinib

HER2 in Breast Cancer Stemness: A Negative Feedback Loop towards Trastuzumab Resistance

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