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    FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4

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    Authors
    McClements, L
    Annett, S
    Yakkundi, A
    O'Rourke, M
    Valentine, A
    Moustafa, N
    Alqudah, A
    Simoes, Bruno M
    Furlong, F
    Short, A
    McIntosh, SA
    McCarthy, HO
    Clarke, Robert B
    Robson, T
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    Affiliation
    Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
    Issue Date
    2019
    
    Metadata
    Show full item record
    Abstract
    BACKGROUND: Optimising breast cancer treatment remains a challenge. Resistance to therapy is a major problem in both ER- and ER+ breast cancer. Tumour recurrence after chemotherapy and/or targeted therapy leads to more aggressive tumours with enhanced metastatic ability. Self-renewing cancer stem cells (CSCs) have been implicated in treatment resistance, recurrence and the development of metastatic disease. METHODS: In this study, we utilised in vitro, in vivo and ex vivo breast cancer models using ER+ MCF-7 and ER- MDA-MB-231 cells, as well as solid and metastatic breast cancer patient samples, to interrogate the effects of FKBPL and its peptide therapeutics on metastasis, endocrine therapy resistant CSCs and DLL4 and Notch4 expression. The effects of FKBPL overexpression or peptide treatment were assessed using a t-test or one-way ANOVA with Dunnett's multiple comparison test. RESULTS: We demonstrated that FKBPL overexpression or treatment with FKBPL-based therapeutics (AD-01, pre-clinical peptide /ALM201, clinical peptide) inhibit i) CSCs in both ER+ and ER- breast cancer, ii) cancer metastasis in a triple negative breast cancer metastasis model and iii) endocrine therapy resistant CSCs in ER+ breast cancer, via modulation of the DLL4 and Notch4 protein and/or mRNA expression. AD-01 was effective at reducing triple negative MDA-MB-231 breast cancer cell migration (n???3, p?<?0.05) and invasion (n???3, p?<?0.001) and this was translated in vivo where AD-01 inhibited breast cancer metastasis in MDA-MB-231-lucD3H1 in vivo model (p?<?0.05). In ER+ MCF-7 cells and primary breast tumour samples, we demonstrated that ALM201 inhibits endocrine therapy resistant mammospheres, representative of CSC content (n???3, p?<?0.05). Whilst an in vivo limiting dilution assay, using SCID mice, demonstrated that ALM201 alone or in combination with tamoxifen was very effective at delaying tumour recurrence by 12 (p?<?0.05) or 21?days (p?<?0.001), respectively, by reducing the number of CSCs. The potential mechanism of action, in addition to CD44, involves downregulation of DLL4 and Notch4. CONCLUSION: This study demonstrates, for the first time, the pre-clinical activity of novel systemic anti-cancer therapeutic peptides, ALM201 and AD-01, in the metastatic setting, and highlights their impact on endocrine therapy resistant CSCs; both areas of unmet clinical need. KEYWORDS: AD-01; ALM201; Breast cancer stem cells; DLL4; Endocrine therapy; Estrogen receptor; FKBPL; Letrozole; Metastasis; Notch4; Tamoxifen; Triple negative breast cancer
    Citation
    McClements L, Annett S, Yakkundi A, O'Rourke M, Valentine A, Moustafa N, et al. FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. BMC Cancer. 2019 Apr 11;19(1):351.
    Journal
    BMC Cancer
    URI
    http://hdl.handle.net/10541/621872
    DOI
    10.1186/s12885-019-5500-0
    PubMed ID
    30975104
    Additional Links
    https://dx.doi.org/10.1186/s12885-019-5500-0
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1186/s12885-019-5500-0
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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