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dc.contributor.authorHugo, HJ
dc.contributor.authorGunasinghe, NPAD
dc.contributor.authorHollier, BG
dc.contributor.authorTanaka, T
dc.contributor.authorBlick, T
dc.contributor.authorToh, A
dc.contributor.authorHill, P
dc.contributor.authorGilles, C
dc.contributor.authorWaltham, M
dc.contributor.authorThompson, EW
dc.date.accessioned2021-07-06T11:08:17Z
dc.date.available2021-07-06T11:08:17Z
dc.date.issued2017
dc.identifier.issn1465-5411en_US
dc.identifier.doi10.1186/s13058-017-0880-zen_US
dc.identifier.urihttp://hdl.handle.net/10072/405718
dc.description.abstractBackground: Epithelial-to-mesenchymal transition (EMT) is associated with downregulated E-cadherin and frequently with decreased proliferation. Proliferation may be restored in secondary metastases by mesenchymal-to-epithelial transition (MET). We tested whether E-cadherin maintains epithelial proliferation in MDA-MB-468 breast cancer cells, facilitating metastatic colonization in severe combined immunodeficiency (SCID) mice. Methods: EMT/MET markers were assessed in xenograft tumors by immunohistochemistry. Stable E-cadherin manipulation was effected by transfection and verified by Western blotting, immunocytochemistry, and quantitative polymerase chain reaction (qPCR). Effects of E-cadherin manipulation on proliferation and chemomigration were assessed in vitro by performing sulforhodamine B assays and Transwell assays, respectively. Invasion was assessed by Matrigel outgrowth; growth in vivo was assessed in SCID mice; and EMT status was assessed by qPCR. Hypoxic response of E-cadherin knockdown cell lines was assessed by qPCR after hypoxic culture. Repeated measures analysis of variance (ANOVA), one- and two-way ANOVA with posttests, and paired Student's t tests were performed to determine significance (p < 0.05). Results: EMT occurred at the necrotic interface of MDA-MB-468 xenografts in regions of hypoxia. Extratumoral deposits (vascular and lymphatic inclusions, local and axillary nodes, and lung metastases) strongly expressed E-cadherin. MDA-MB-468 cells overexpressing E-cadherin were more proliferative and less migratory in vitro, whereas E-cadherin knockdown (short hairpin CDH1 [shCDH1]) cells were more migratory and invasive, less proliferative, and took longer to form tumors. shCDH1-MDA-MB-468 xenografts did not contain the hypoxia-induced necrotic areas observed in wild-type (WT) and shSCR-MDA-MB-468 tumors, but they did not exhibit an impaired hypoxic response in vitro. Although vimentin expression was not stimulated by E-cadherin knockdown in 2D or 3D cultures, xenografts of these cells were globally vimentin-positive rather than exhibiting regional EMT, and they expressed higher SNA1 than their in vitro counterparts. E-cadherin suppression caused a trend toward reduced lung metastasis, whereas E-cadherin overexpression resulted in the reverse trend, consistent with the increased proliferation rate and predominantly epithelial phenotype of MDA-MB-468 cells outside the primary xenograft. This was also originally observed in WT xenografts. Furthermore, we found that patients with breast cancer that expressed E-cadherin were more likely to have metastases. Conclusions: E-cadherin expression promotes growth of primary breast tumors and conceivably the formation of metastases, supporting a role for MET in metastasis. E-cadherin needs to be reevaluated as a tumor suppressor.en_US
dc.description.peerreviewedYesen_US
dc.languageengen_US
dc.publisherSpringer Science and Business Media LLCen_US
dc.relation.ispartofpagefrom86en_US
dc.relation.ispartofissue1en_US
dc.relation.ispartofjournalBreast Cancer Researchen_US
dc.relation.ispartofvolume19en_US
dc.subject.fieldofresearchCancer Therapy (excl. Chemotherapy and Radiation Therapy)en_US
dc.subject.fieldofresearchCancer Cell Biologyen_US
dc.subject.fieldofresearchOncology and Carcinogenesisen_US
dc.subject.fieldofresearchcode111204en_US
dc.subject.fieldofresearchcode111201en_US
dc.subject.fieldofresearchcode1112en_US
dc.subject.keywordsBreast canceren_US
dc.subject.keywordsE-cadherinen_US
dc.subject.keywordsEpithelial-mesenchymal plasticityen_US
dc.subject.keywordsEpithelial-to-mesenchymal transitionen_US
dc.subject.keywordsMetastasisen_US
dc.titleEpithelial requirement for in vitro proliferation and xenograft growth and metastasis of MDA-MB-468 human breast cancer cells: Oncogenic rather than tumor-suppressive role of E-cadherinen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationHugo, HJ; Gunasinghe, NPAD; Hollier, BG; Tanaka, T; Blick, T; Toh, A; Hill, P; Gilles, C; Waltham, M; Thompson, EW, Epithelial requirement for in vitro proliferation and xenograft growth and metastasis of MDA-MB-468 human breast cancer cells: Oncogenic rather than tumor-suppressive role of E-cadherin, Breast Cancer Research, 2017, 19 (1), pp. 86en_US
dcterms.dateAccepted2017-07-07
dcterms.licensehttp://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-07-06T01:19:58Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en_US
gro.hasfulltextFull Text
gro.griffith.authorHugo, Honor J.


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