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  1. Article ; Online: Evaluation of ABT-751, a novel anti-mitotic agent able to overcome multi-drug resistance, in melanoma cells.

    Mahgoub, Thamir M / Jordan, Emmet J / Mahdi, Amira F / Oettl, Veronika / Huefner, Stefanie / O'Donovan, Norma / Crown, John / Collins, Denis M

    Cancer chemotherapy and pharmacology

    2024  Volume 93, Issue 5, Page(s) 427–437

    Abstract: Purpose: Drug efflux transporter associated multi-drug resistance (MDR) is a potential limitation in the use of taxane chemotherapies for the treatment of metastatic melanoma. ABT-751 is an orally bioavailable microtubule-binding agent capable of ... ...

    Abstract Purpose: Drug efflux transporter associated multi-drug resistance (MDR) is a potential limitation in the use of taxane chemotherapies for the treatment of metastatic melanoma. ABT-751 is an orally bioavailable microtubule-binding agent capable of overcoming MDR and proposed as an alternative to taxane-based therapies.
    Methods: This study compares ABT-751 to taxanes in vitro, utilizing seven melanoma cell line models, publicly available gene expression and drug sensitivity databases, a lung cancer cell line model of MDR drug efflux transporter overexpression (DLKP-A), and drug efflux transporter ATPase assays.
    Results: Melanoma cell lines exhibit a low but variable protein and RNA expression of drug efflux transporters P-gp, BCRP, and MDR3. Expression of P-gp and MDR3 correlates with sensitivity to taxanes, but not to ABT-751. The anti-proliferative IC
    Conclusion: Our study confirms that ABT-751 is active against melanoma cell lines and models of MDR at physiologically relevant concentrations, it inhibits P-gp ATPase activity, and it may be a BCRP and/or MDR3 substrate. ABT-751 warrants further investigation alone or in tandem with other drug efflux transporter inhibitors for hard-to-treat MDR melanoma.
    MeSH term(s) Humans ; Melanoma/drug therapy ; Melanoma/pathology ; Melanoma/genetics ; Melanoma/metabolism ; Drug Resistance, Neoplasm/drug effects ; Sulfonamides/pharmacology ; Cell Line, Tumor ; Drug Resistance, Multiple/drug effects ; Taxoids/pharmacology ; Cell Proliferation/drug effects ; Antimitotic Agents/pharmacology ; Antineoplastic Agents/pharmacology ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors
    Chemical Substances Sulfonamides ; ABT751 ; Taxoids ; Antimitotic Agents ; Antineoplastic Agents ; ATP Binding Cassette Transporter, Subfamily G, Member 2
    Language English
    Publishing date 2024-01-16
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 6820-2
    ISSN 1432-0843 ; 0344-5704 ; 0943-9404
    ISSN (online) 1432-0843
    ISSN 0344-5704 ; 0943-9404
    DOI 10.1007/s00280-023-04624-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Collagen-I influences the post-translational regulation, binding partners and role of Annexin A2 in breast cancer progression.

    Mahdi, Amira F / Nolan, Joanne / O'Connor, Ruth Í / Lowery, Aoife J / Allardyce, Joanna M / Kiely, Patrick A / McGourty, Kieran

    Frontiers in oncology

    2023  Volume 13, Page(s) 1270436

    Abstract: Introduction: The extracellular matrix (ECM) has been heavily implicated in the development and progression of cancer. We have previously shown that Annexin A2 is integral in the migration and invasion of breast cancer cells and in the clinical ... ...

    Abstract Introduction: The extracellular matrix (ECM) has been heavily implicated in the development and progression of cancer. We have previously shown that Annexin A2 is integral in the migration and invasion of breast cancer cells and in the clinical progression of ER-negative breast cancer, processes which are highly influenced by the surrounding tumor microenvironment and ECM.
    Methods: We investigated how modulations of the ECM may affect the role of Annexin A2 in MDA-MB-231 breast cancer cells using western blotting, immunofluorescent confocal microscopy and immuno-precipitation mass spectrometry techniques.
    Results: We have shown that the presence of collagen-I, the main constituent of the ECM, increases the post-translational phosphorylation of Annexin A2 and subsequently causes the translocation of Annexin A2 to the extracellular surface. In the presence of collagen-I, we identified fibronectin as a novel interactor of Annexin A2, using mass spectrometry analysis. We then demonstrated that reducing Annexin A2 expression decreases the degradation of fibronectin by cancer cells and this effect on fibronectin turnover is increased according to collagen-I abundance.
    Discussion: Our results suggest that Annexin A2's role in promoting cancer progression is mediated by collagen-I and Annexin A2 maybe a therapeutic target in the bi-directional cross-talk between cancer cells and ECM remodeling that supports metastatic cancer progression.
    Language English
    Publishing date 2023-10-24
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2023.1270436
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Collagen and fibronectin promote an aggressive cancer phenotype in breast cancer cells but drive autonomous gene expression patterns.

    Nolan, Joanne / Mahdi, Amira F / Dunne, Colum P / Kiely, Patrick A

    Gene

    2020  Volume 761, Page(s) 145024

    Abstract: Understanding how various pathologies of breast cancer respond to their environment may be imperative in the creation of novel therapeutic targets. Central to the organisation and behaviour of cells within the tumour microenvironment is the extracellular ...

    Abstract Understanding how various pathologies of breast cancer respond to their environment may be imperative in the creation of novel therapeutic targets. Central to the organisation and behaviour of cells within the tumour microenvironment is the extracellular matrix (ECM), a meshwork of fibrous proteins and glycoproteins that directly influences cell behaviour and the bioavailability of signalling molecules. Our appreciation on how the composition of the ECM can influence cancer behaviour has evolved significantly and although we are highly cognisant of the dramatic impact the ECM can have on cancer cell behaviour, we continue to neglect this during diagnosis and treatment. In the following study, we aimed to identify how three breast cancer cell lines respond functionally and genetically to common components of the ECM. Using real time and end point assays we have identified similar patterns of behaviour among the three breast cancer cell lines in response to commonly found ECM components of the breast. Using a selected gene panel, we have been able to identify cell line specific changes in gene differentiation when breast cancer cells are in contact with these elements. Although the response of our cells to these elements differ at the genetic level, their functional responses are consistent. This work adds to the growing arguments that highlight a need for histologically assessing ECM composition of breast tumours. In particular monitoring of fibrous protein deposition at the site of malignancy could provide critical information during clinical assessment influencing disease prognosis and treatment decisions for breast cancer patients.
    MeSH term(s) Breast/pathology ; Breast Neoplasms/genetics ; Cell Line, Tumor ; Collagen/genetics ; Collagen/metabolism ; Collagen Type I/genetics ; Extracellular Matrix/metabolism ; Extracellular Matrix Proteins/genetics ; Female ; Fibronectins/genetics ; Fibronectins/metabolism ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic/genetics ; Genotype ; Glycoproteins/genetics ; Humans ; Phenotype ; Prognosis ; Signal Transduction ; Tumor Microenvironment
    Chemical Substances Collagen Type I ; Extracellular Matrix Proteins ; FN1 protein, human ; Fibronectins ; Glycoproteins ; Collagen (9007-34-5)
    Language English
    Publishing date 2020-08-02
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 391792-7
    ISSN 1879-0038 ; 0378-1119
    ISSN (online) 1879-0038
    ISSN 0378-1119
    DOI 10.1016/j.gene.2020.145024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Collagen and fibronectin promote an aggressive cancer phenotype in breast cancer cells but drive autonomous gene expression patterns

    Nolan, Joanne / Mahdi, Amira F / Dunne, Colum P / Kiely, Patrick A

    Gene. 2020 Nov. 30, v. 761

    2020  

    Abstract: Understanding how various pathologies of breast cancer respond to their environment may be imperative in the creation of novel therapeutic targets. Central to the organisation and behaviour of cells within the tumour microenvironment is the extracellular ...

    Abstract Understanding how various pathologies of breast cancer respond to their environment may be imperative in the creation of novel therapeutic targets. Central to the organisation and behaviour of cells within the tumour microenvironment is the extracellular matrix (ECM), a meshwork of fibrous proteins and glycoproteins that directly influences cell behaviour and the bioavailability of signalling molecules. Our appreciation on how the composition of the ECM can influence cancer behaviour has evolved significantly and although we are highly cognisant of the dramatic impact the ECM can have on cancer cell behaviour, we continue to neglect this during diagnosis and treatment. In the following study, we aimed to identify how three breast cancer cell lines respond functionally and genetically to common components of the ECM. Using real time and end point assays we have identified similar patterns of behaviour among the three breast cancer cell lines in response to commonly found ECM components of the breast. Using a selected gene panel, we have been able to identify cell line specific changes in gene differentiation when breast cancer cells are in contact with these elements. Although the response of our cells to these elements differ at the genetic level, their functional responses are consistent. This work adds to the growing arguments that highlight a need for histologically assessing ECM composition of breast tumours. In particular monitoring of fibrous protein deposition at the site of malignancy could provide critical information during clinical assessment influencing disease prognosis and treatment decisions for breast cancer patients.
    Keywords assays ; behavior ; bioavailability ; breast neoplasms ; breasts ; cell lines ; chemical elements ; collagen ; environment ; extracellular matrix ; fibronectins ; gene expression regulation ; genes ; glycoproteins ; information ; monitoring ; neoplasm cells ; patients ; phenotype ; prognosis ; protein deposition ; therapeutics
    Language English
    Dates of publication 2020-1130
    Publishing place Elsevier B.V.
    Document type Article
    Note NAL-light
    ZDB-ID 391792-7
    ISSN 1879-0038 ; 0378-1119
    ISSN (online) 1879-0038
    ISSN 0378-1119
    DOI 10.1016/j.gene.2020.145024
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Expression of Annexin A2 Promotes Cancer Progression in Estrogen Receptor Negative Breast Cancers.

    Mahdi, Amira F / Malacrida, Beatrice / Nolan, Joanne / McCumiskey, Mary E / Merrigan, Anne B / Lal, Ashish / Tormey, Shona / Lowery, Aoife J / McGourty, Kieran / Kiely, Patrick A

    Cells

    2020  Volume 9, Issue 7

    Abstract: When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that ... ...

    Abstract When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized during the metastatic processes of migration and invasion will greatly enhance our understanding of breast cancer progression. We conducted a mass spectrometry screen following bioorthogonal noncanonical amino acid tagging to elucidate changes in the nascent proteome that occur during epidermal growth factor stimulation in migrating and invading cells. Annexin A2 was identified in this screen and subsequent examination of breast cancer cell lines revealed that Annexin A2 is specifically upregulated in estrogen receptor negative (ER-) cell lines. Furthermore, siRNA knockdown showed that Annexin A2 expression promotes the proliferation, wound healing and directional migration of breast cancer cells. In patients, Annexin A2 expression is increased in ER- breast cancer subtypes. Additionally, high Annexin A2 expression confers a higher probability of distant metastasis specifically for ER- patients. This work establishes a pivotal role of Annexin A2 in breast cancer progression and identifies Annexin A2 as a potential therapeutic target for the more aggressive and harder to treat ER- subtype.
    MeSH term(s) Annexin A2/genetics ; Annexin A2/metabolism ; Blotting, Western ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Movement/physiology ; Cell Proliferation/genetics ; Cell Proliferation/physiology ; Electrophoresis, Polyacrylamide Gel ; Female ; Humans ; Immunoprecipitation ; MCF-7 Cells ; Mass Spectrometry ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Receptors, Estrogen/genetics ; Receptors, Estrogen/metabolism
    Chemical Substances Annexin A2 ; Carrier Proteins ; RNA, Small Interfering ; Receptors, Estrogen ; estrophilin
    Language English
    Publishing date 2020-06-30
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9071582
    Database MEDical Literature Analysis and Retrieval System OnLINE

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