Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells

Canfield, Kaleigh; Li, Jiaqi; Wilkins, Owen M.; Morrison, Meghan M.; Ung, Matthew; Wells, Wendy A.; Williams, Charlotte R.; Liby, Karen T.; Vullhorst, Detlef; Buonanno, Andrés; Hu, Huizhong; Schiff, Rachel; Cook, Rebecca S.; Kurokawa, Manabu

doi:10.4161/15384101.2014.994966

Cited by 70 publications

(76 citation statements)

References 35 publications

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“…45 As a most frequently hyperactivated signaling in plenty of malignancies, AKT pathway mediates cell survival and chemoresistance. 11 Full activation of AKT requires phosphoinositidedependent kinase 1 (PDK1) and mammalian target of rapamycin complex 2 (mTORC2) mediated phosphorylation at both Thr308 and Ser473.…”

Section: Discussionmentioning

confidence: 99%

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

et al. 2016

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Long noncoding RNAs act as crucial regulators in plenty of human cancers, yet their potential roles and molecular mechanisms in chemoresistance are poorly understood. This study showed that a novel lncRNA, long intergenic noncoding RNA 152 (Linc00152 ), promoted tumor progression and conferred resistance to oxaliplatin (L-OHP)-induced apoptosis in vitro and in vivo. It antagonized chemosensitivity through acting as a competing endogenous RNA to modulate the expression of miR-193a-3p, and then erb-b2 receptor tyrosine kinase 4 (ERBB4). Knockdown of ERBB4 in colon cancer cells decreased AKT phosphorylation, which resulted in decreased L-OHP resistance. Consistent with above findings, the specific AKT signaling inhibitor and activator were used, respectively, which demonstrated that Linc00152 contributed to L-OHP resistance at least partly through activating AKT pathway. Further studies indicated that Linc00152 was increased and appeared to be an independent prognostic factor for decreased survival and increased disease recurrence in stage II and III colon cancer patients undergoing L-OHP-based chemotherapy after surgery. Collectively, our findings established Linc00152 as a candidate prognostic indicator of outcome and drug responsiveness in colon cancer patients, and the involvement of competing endogenous RNAs mechanism in Linc00152/ miR-193a-3p/ERBB4/AKT signaling axis may provide a novel choice in the investigation of drug resistance.

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Section: Discussionmentioning

confidence: 99%

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

et al. 2016

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“…[31][32][33][34]38 More recently, ERBB4 has been implicated in mediating acquired resistance to ERBB2 inhibitors and in protecting epidermal growth factor receptor from degradation in breast cancer cells. 39,40 Conversely, COL29A1 encodes for the collagen VI a chain COL6A5, an extracellular matrix protein with critical roles in maintaining muscle and skin integrity. 41 In addition to structural functions, evidence suggests that collagen VI has growthstimulatory and prosurvival effects.…”

Section: Discussionmentioning

confidence: 99%

Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts

Scarfò

Pellegrino

Mereu

et al. 2016

Blood

105

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• Endogenous intronic long terminal repeats promote the ectopic expression of truncated ERBB4 transcripts in 24% of ALK-negative ALCL.• The expression of ERBB4-aberrant transcripts defines a new subclass of ALKnegative ALCL and may contribute to ALCL transformation.Anaplastic large-cell lymphoma (ALCL) is a clinical and biological heterogeneous disease that includes systemic anaplastic lymphoma kinase (ALK)-positive and ALKnegative entities. To discover biomarkers and/or genes involved in ALK-negative ALCL pathogenesis, we applied the cancer outlier profile analysis algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T cells. Ectopic coexpression of ERBB4 and COL29A1 genes was detected in 24% of ALK-negative ALCL patients. RNA sequencing and 59 RNA ligase-mediated rapid amplification of complementary DNA ends identified 2 novel ERBB4-truncated transcripts displaying intronic transcription start sites. By luciferase assays, we defined that the expression of ERBB4-aberrant transcripts is promoted by endogenous intronic long terminal repeats. ERBB4 expression was confirmed at the protein level by western blot analysis and immunohistochemistry. Lastly, we demonstrated that ERBB4-truncated forms show oncogenic potentials and that ERBB4 pharmacologic inhibition partially controls ALCL cell growth and disease progression in an ERBB4-positive patient-derived tumorgraft model. In conclusion, we identified a new subclass of ALK-negative ALCL characterized by aberrant expression of ERBB4-truncated transcripts carrying intronic 59 untranslated regions. (Blood. 2016;127(2):221-232)

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“…There are potentially oncogenic ERBB4 mutations in non-small cell lung cancer (9), and it has been reported that HER4 is overexpressed in human colon cancer and enhances cellular transformation (10). In addition, HER4 promotes breast cancer cell proliferation, mediates acquired resistance to ERBB2 inhibitors and may serve as a prognostic marker in patients with breast cancer (11)(12)(13)(14). However, the role of HER4 in CRC remains to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

HER4 isoform CYT2 and its ligand NRG1III are expressed at high levels in human colorectal cancer

et al. 2018

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Abstract. The present study aimed to evaluate the expression of human epidermal growth factor receptor (HER4) isoforms and their ligand neuregulin 1 (NRG1) isoforms in human primary colorectal cancer (CRC). The mRNA expression of HER4 isoforms JM-a, JM-b, CYT1 and CYT2, and their ligand isoforms NRG1 I, II and III in CRC tissues and adjacent normal tissues were quantified by reverse transcription-quantitative polymerase chain reaction analysis. Univariate analysis and logistic regression analysis were performed to analyze the association between HER4 and NRG1 expression and lymph node metastasis in CRC. The expression levels of CYT1 (P=0.002), CYT2 (P=0.002) and NRG1 type III (P<0.001) were significantly higher in the CRC tissues than in the adjacent normal tissues. The expression of CYT2 was correlated with tumor stage (P=0.018), lymph node status (P=0.015) and tumor-node-metastasis (P=0.038) in CRC. The expression of NRG1III was correlated with lymph node metastasis, and the expression of CYT2 was associated with the expression of NRG1III (r=0.691, P<0.01). The logistic regression analysis indicated that expression of CYT2 >50 was a risk factor for lymph node metastasis in CRC. In conclusion the expression levels of CYT1, CYT2 and NRG1III were upregulated in CRC. An expression of CYT-2 >50 was identified as a risk factor for lymph node metastasis in CRC. Therefore, CY-2 and NRG1III may be involved in the progression of CRC.

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Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells

Cited by 70 publications

References 35 publications

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts

HER4 isoform CYT2 and its ligand NRG1III are expressed at high levels in human colorectal cancer

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