Nuclear ErbB-2: a Novel Therapeutic Target in ErbB-2-Positive Breast Cancer?

Russo, R; Chervo, María Florencia; Madera, Santiago; Elizalde, Patricia V.

doi:10.1007/s12672-018-0356-3

Cited by 10 publications

(11 citation statements)

References 47 publications

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“…[52,53] Nuclear EGFR is a novel target for breast cancer. [54] In the present study, we have studied the effects of EAD cellular localization of EGFR, and the results indicated that EAD could minimize the expression of membranous and nuclear EGFR. It was reported that EGFR is F I G U R E 11 A summary of the cellular events altered by EAD to exert anticancer effects in MDA-MB-231 cells: (1) by inducing apoptosis, (2) inducing anoikis, (3) inhibiting metastasis, (4) inducing cell cycle arrest, (5) inhibiting cellular metabolism, (6) inhibiting NF-KB nuclear translocation, (7) binding to cell surface EGFR and inhibiting downstream signal transduction, (8) inhibiting the nuclear expression of EGFR.…”

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 88%

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Epoxyazadiradione induced apoptosis/anoikis in triple‐negative breast cancer cells, MDA‐MB‐231, by modulating diverse cellular effects

Lakshmi

Jalaja

Sasidhar

et al. 2021

J Biochem & Molecular Tox

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Triple-negative breast cancer (TNBC) is one of the most aggressive forms of its kind, which accounts for 15-20% of all breast cancers. As this cancer form lacks hormone receptors, targeted chemotherapy remains the best treatment option. Apoptosis and anoikis (detachment-induced cell death) induction by small molecules can prevent TNBC metastasis to a greater extent. Epoxyazadiradione (EAD) is a limonoid from the neem plant with an anticancer property. Here, we demonstrate that EAD induced mitochondria-mediated apoptosis and anoikis in TNBC cells (MDA-MB-231). Apart from this, it promotes antimigration, inhibition of colony formation, downregulation of MMP-9 and fibronectin, induction of G2/M phase arrest with downregulation of cyclin A2/cdk2, interference in cellular metabolism, and inhibition of nuclear factor kappa-B (NF-KB) nuclear translocation. Moreover, a significant reduction is observed in the expression of EGFR on the plasma membrane and nucleus upon treatment with EAD. Among the diverse cellular effects, anoikis induction, metabolic interference, and downregulation of membrane/nuclear EGFR expression by EAD are reported here for the first time. To summarize, EAD targets multiple cellular events to induce growth arrest in TNBC, and hence can be developed into the best antineoplastic agent in the future.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 88%

Epoxyazadiradione induced apoptosis/anoikis in triple‐negative breast cancer cells, MDA‐MB‐231, by modulating diverse cellular effects

Lakshmi

Jalaja

Sasidhar

et al. 2021

J Biochem & Molecular Tox

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“…The overexpression of HER2 and HSP27 proteins in BT-TR cells was found not only in their sub-cytoplasmic fraction, but also in the sub-nuclear compartment ( Figure 5 A), inducing the distinctive role of nuclear HER2 as a transcriptional coactivator that promotes cyclin D1 expression ( Figure 5 B). Diverse studies have previously reported that the nuclear fraction of HER2 is involved in cell growth, metastasis, invasion, and resistance to various chemotherapeutic agents in BC [ 49 ]. Particularly for TZMB, HER2 in the nucleus distinctively assembles a STAT3/HER2/HER3 nuclear complex that triggers the promoter activity of CCND1 to escape the growth inhibitory effect of TZMB [ 50 ].…”

Section: Resultsmentioning

confidence: 99%

Specific Roles of HSP27 S15 Phosphorylation Augmenting the Nuclear Function of HER2 to Promote Trastuzumab Resistance

Hwang

Choi

Seo

et al. 2020

Cancers

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Trastuzumab (TZMB) is widely used as first line therapy for breast cancer (BC) patients overexpressing human epidermal growth factor receptor 2 (HER2). Despite its clinical benefits, many patients suffer from primary or secondary resistance to this drug within one year. As diverse molecular mechanisms occur contemporaneously during the resistance development, we focused on elucidating the role of heat shock protein 27 (HSP27) in TZMB-resistance, as this protein simultaneously regulates the function of diverse client molecules that are involved in the resistance mechanism. By extensively utilizing TZMB-refractory breast cancer cell lines transduced with diverse phosphovariants of HSP27, our study newly revealed that specific phosphorylation of HSP27 at S15 promoted its S78 phosphorylation and served as key mediator to promote direct interactions that increase the stability of HER2 and protein kinase B (AKT). This phosphorylation promoted nuclear translocation of HER2, enhancing the distinct nuclear function of HER2 that promoted AKT activation and cyclin D1 expression. Co-administration of TZMB and a functional inhibitor of HSP27, J2, significantly reduced the S15/78 phosphorylation of HSP27, which downregulated HER2 and its downstream signals, sensitizing TZMB-refractory cell, and JIMT1-xenograft mouse models to TZMB. Collectively, p-HSP27S15 could serve as a valuable predictive marker and also a therapeutic target for TZMB-resistance.

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“…Nuclear ERBB2 has been reported to be involved in tumor growth and metastasis as well as resistance to anti‐ERBB2 treatment in breast cancers 30,36,39,55,57,59 . C‐terminal fragments of ERBB2 generated by alternative initiation from the internal AUG codon have also been shown to have tumorigenic property 42,60,61 .…”

Section: Discussionmentioning

confidence: 99%

“…The presence of nuclear forms of RTKs, including the four members of the EGFR family, has been revealed since the last two decades 26‐30 and several mechanisms for the nuclear translocation and the function of those nuclear RTKs have been reported 27‐34 . Interestingly, recent studies shed new light on the role played by the nuclear form of ERBB2 in the resistance to anti‐ERBB2 treatments 35‐39 …”

Section: Introductionmentioning

confidence: 99%

ERBB2b mRNA isoform encodes a nuclear variant of the ERBB2 oncogene in breast cancer

Hua

Bergon

Cauchy

et al. 2020

J of Cellular Biochemistry

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The presence of nuclear ERBB2 receptor-type tyrosine kinase is one of the causes of the resistance to membrane ERBB2-targeted therapy in breast cancers. It has been previously reported that this nuclear location arises through at least two different mechanisms: proteolytic shedding of the extracellular domain of the full-length receptor and translation of the messenger RNA (mRNA)-encoding ERBB2 from internal initiation codons. Here, we report a new mechanism and function where a significant portion of nuclear ERBB2 results from the translation of the variant ERBB2 mRNA under the transcriptional control of a distal promoter that is actively used in breast cancer cells. We show that both membrane ERBB2a and nuclear ERBB2b isoforms are prevalently expressed in breast cancer cell lines and carcinoma samples. The ERBB2b isoform, which is translated from mRNA variant 2, can directly translocate into the nucleus due to the lack of the signal peptide which is required for an intermediate membrane location. Small interfering RNAmediated gene silencing showed that ERBB2b can repress ERBB2a expression, encoded by variant 1, whereas ERBB2a activates ERBB2b. Nuclear ERBB2 binding to its own promoter was revealed by chromatin immunoprecipitation assay. Altogether, our results provide new insights into the origin and function of nuclear ERBB2 where it can participate at the same time in a positive or a negative feedback autoregulatory loop, dependent on which of its promoters this bona fide transcription factor is acting. They also provide a new understanding for the resistance to therapies targeting the membrane-anchored ERBB2 in breast cancer.

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Nuclear ErbB-2: a Novel Therapeutic Target in ErbB-2-Positive Breast Cancer?

Cited by 10 publications

References 47 publications

Epoxyazadiradione induced apoptosis/anoikis in triple‐negative breast cancer cells, MDA‐MB‐231, by modulating diverse cellular effects

Epoxyazadiradione induced apoptosis/anoikis in triple‐negative breast cancer cells, MDA‐MB‐231, by modulating diverse cellular effects

Specific Roles of HSP27 S15 Phosphorylation Augmenting the Nuclear Function of HER2 to Promote Trastuzumab Resistance

ERBB2b mRNA isoform encodes a nuclear variant of the ERBB2 oncogene in breast cancer

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