Pathobiological implications of the d16HER2 splice variant for stemness and aggressiveness of HER2-positive breast cancer

Castagnoli, Lorenzo; Ghedini, Gaia C.; Koschorke, Ada; Triulzi, Tiziana; Dugo, Matteo; Gasparini, Patrizia; Casalini, Patrizia; Palladini, Ariannna; Iezzi, Manuela; Lamolinara, Alessia; Lollini, Pier‐Luigi; Nanni, Patrizia; Chiodoni, Claudia; Tagliabue, Elda; Pupa, Serenella M.

doi:10.1038/onc.2016.338

Cited by 40 publications

(51 citation statements)

References 44 publications

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“…These genes included epigenetic regulators (for example, JMJD3), genes that control tumor stemness in OC malignancies (for example, HER2), cell proliferation (for example, RB1), apoptosis (for example, BCL-2) and metastasis (for example, MYCN). [12][13][14][15] We found that JMJD3, BCL-2, MYCN, and HER2 levels strongly decreased with Fp-PCN PAC+CAR treatment (Fig. 6C).…”

Section: Jmjd3 As a Novel Target Of Fp-pcn Pac+car In Human Oc Cellsmentioning

confidence: 76%

Multifunctional nanoparticles for co-delivery of paclitaxel and carboplatin against ovarian cancer by inactivating the JMJD3-HER2 axis

Wang

Huang

et al. 2017

Nanoscale

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a Ovarian cancer (OC) is the most lethal gynecologic cancer. Survival statistics have show no significant developments over the last three decades, highlighting the fact that current therapeutic strategies require substantial improvements. In this study, we designed a novel folic acid-PEG-conjugated p-phosphonated calix[4]arene nanoparticle (Fp-PCN) for the simultaneous delivery of paclitaxel (PAC) and carboplatin (CAR) at an optimal ratio (5 : 1, mol : mol) to utilize their potential synergistic effect against OC cells.The Fp-PCNs loaded with PAC and CAR (Fp-PCN PAC+CAR ) resulted in a remarkable efficacy in the suppression of OC, both in vitro and in vivo. Compared to free drugs, Fp-PCN PAC+CAR showed stronger apoptosis induction as well as invasion and self-renewal capacity suppression in SKOV-3 cells. The molecular mechanism to address the synergism is that Fp-PCN PAC+CAR downregulated JMJD3 expression to modulate the H3K27me3 epigenetic mark of the promoters of HER2 and MYCN. Furthermore, the expressions of JMJD3 and HER2 were significantly associated with poor outcomes for ovarian patients.Our study demonstrates that co-delivery of PAC and CAR can be achieved with the Fp-PCNs, and reveals a previously unrecognized and unexpected role of the JMJD3-HER2 signaling axis in PAC and CAR treatment of OC.

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Section: Jmjd3 As a Novel Target Of Fp-pcn Pac+car In Human Oc Cellsmentioning

confidence: 76%

Multifunctional nanoparticles for co-delivery of paclitaxel and carboplatin against ovarian cancer by inactivating the JMJD3-HER2 axis

Wang

Huang

et al. 2017

Nanoscale

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“…A variety of potential molecular mechanisms of resistance to trastuzumab have previously been published, [9][10][11][12] and the vast majority involve the biological functions of breast cancer stem cells (BCSCs). 12,13 Cancer stem cells (CSCs) are a rare fraction of tumour cells that have the abilities of self-renewal, unlimited proliferation and multi-potent differentiation. 14 Like normal tissues, tumour tissues are composed of a variety of heterogeneous tumour cells and originate from corresponding stem cells.…”

mentioning

confidence: 99%

miR‐200c suppresses stemness and increases cellular sensitivity to trastuzumab in HER2+ breast cancer

Tang

Song

et al. 2019

J Cellular Molecular Medi

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Resistance to trastuzumab remains a major obstacle in HER2‐overexpressing breast cancer treatment. miR‐200c is important for many functions in cancer stem cells (CSCs), including tumour recurrence, metastasis and resistance. We hypothesized that miR‐200c contributes to trastuzumab resistance and stemness maintenance in HER2‐overexpressing breast cancer. In this study, we used HER2‐positive SKBR3, HER2‐negative MCF‐7, and their CD44+CD24− phenotype mammospheres SKBR3‐S and MCF‐7‐S to verify. Our results demonstrated that miR‐200c was weakly expressed in breast cancer cell lines and cell line stem cells. Overexpression of miR‐200c resulted in a significant reduction in the number of tumour spheres formed and the population of CD44+CD24− phenotype mammospheres in SKBR3‐S. Combining miR‐200c with trastuzumab can significantly reduce proliferation and increase apoptosis of SKBR3 and SKBR3‐S. Overexpression of miR‐200c also eliminated its downstream target genes. These genes were highly expressed and positively related in breast cancer patients. Overexpression of miR‐200c also improved the malignant progression of SKBR3‐S and SKBR3 in vivo. miR‐200c plays an important role in the maintenance of the CSC‐like phenotype and increases drug sensitivity to trastuzumab in HER2+ cells and stem cells.

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“…90 If patients are first diagnosed with later stages, the 5 year survival rate can be as low as 27%. 95 In fact, it is thought that resistance to monoclonal antibody treatments may be due to inability to bind to this variant form of HER2. For example, the tyrosine kinase receptor HER2 is thought to be overexpressed in up to 30% of patients and is correlated with more aggressive cancer and subsequently increased mortality.…”

Section: Filamentous Phagementioning

confidence: 99%

“…94 Because this variant is found in a majority of patients with HER2-positive breast cancer, it is an attractive target for immunotherapy. 95 In fact, it is thought that resistance to monoclonal antibody treatments may be due to inability to bind to this variant form of HER2. 96 One group created a DNA vaccination that encoded the extracellular and transmembrane domains of Δ16HER2 and demonstrated that following prophylactic immunization, mice were 100% protected from challenge with Δ16HER2-expressing tumor cells for up to 100 days.…”

Section: Filamentous Phagementioning

confidence: 99%

Phage display as a tool for vaccine and immunotherapy development

Hess

Jewell

2019

Bioengineering & Transla Med

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Bacteriophages, or phages, are viruses that specifically infect bacteria and coopt the cellular machinery to create more phage proteins, eventually resulting in the release of new phage particles. Phages are heavily utilized in bioengineering for applications ranging from tissue engineering scaffolds to immune signal delivery. Of specific interest to vaccines and immunotherapies, phages have demonstrated an ability to activate both the innate and adaptive immune systems. The genome of these viral particles can be harnessed for DNA vaccination, or the surface proteins can be exploited for antigen display. More specifically, genes that encode an antigen of interest can be spliced into the phage genome, allowing antigenic proteins or peptides to be displayed by fusion to phage capsid proteins. Phages therefore present antigens to immune cells in a highly ordered and repetitive manner. This review discusses the use of phage with adjuvanting activity as antigen delivery vehicles for vaccination against infectious disease and cancer. K E Y W O R D S bacteriophage, biomaterials, drug delivery, immunology, nanotechnology, phage display, vaccine 1 | INTRODUCTION Bacteriophages, or phages, are prokaryotic viruses that specifically infect bacteria, and are the most abundant life form on earth. 1 Phages were first discovered in the early 20th century and noted for their antibacterial activity. The practice of administering phages (i.e., phage therapy) to patients suffering from bacterial infections began shortly after their discovery, but was controversial largely due to lack of mechanistic knowledge and variable success rates. In fact, the treatment was largely abandoned upon the discovery of antibiotics. 2 Research in this field was reenergized, however, following the development of phage display systems in 1985. 3 George Smith, a chemist at the University of Missouri, demonstrated fusion of peptides to the outer (i.e., capsid) proteins of phages enabling surface display. This work, for which Smith shared a Nobel Prize in 2018, laid the ground work for affinity selection, epitope mapping, and antibody discovery. Since this time, phages have been an important tool for the bioengineering field, exploited for a range of applications including theranostics, 4 batteries, 5,6 drug delivery, 7 and vaccine development. 1Phages are one of many nanotechnologies being investigated for these applications. This review will focus on the advantages that phages provide to the nanomedicine field, specifically vaccination and immunotherapy. Nanomedicine ranges from diagnostics to treatments and relies on the fields of biomedical and chemical engineering,

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Pathobiological implications of the d16HER2 splice variant for stemness and aggressiveness of HER2-positive breast cancer

Cited by 40 publications

References 44 publications

Multifunctional nanoparticles for co-delivery of paclitaxel and carboplatin against ovarian cancer by inactivating the JMJD3-HER2 axis

Multifunctional nanoparticles for co-delivery of paclitaxel and carboplatin against ovarian cancer by inactivating the JMJD3-HER2 axis

miR‐200c suppresses stemness and increases cellular sensitivity to trastuzumab in HER2+ breast cancer

Phage display as a tool for vaccine and immunotherapy development

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