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dc.contributor.authorLee, Connie Wing-Ching
dc.contributor.authorRaskett, Christopher M.
dc.contributor.authorPrudovsky, Igor
dc.contributor.authorAltieri, Dario C.
dc.date2022-08-11T08:09:37.000
dc.date.accessioned2022-08-23T16:38:00Z
dc.date.available2022-08-23T16:38:00Z
dc.date.issued2008-07-03
dc.date.submitted2009-11-03
dc.identifier.citation<p>Cancer Res. 2008 Jul 1;68(13):5273-81. <a href="http://dx.doi.org/10.1158/0008-5472.CAN-07-6673">Link to article on publisher's site</a></p>
dc.identifier.issn1538-7445 (Electronic)
dc.identifier.doi10.1158/0008-5472.CAN-07-6673
dc.identifier.pmid18593928
dc.identifier.urihttp://hdl.handle.net/20.500.14038/39150
dc.description.abstractDespite progress in the management of breast cancer, the molecular underpinnings of clinically aggressive subtypes of the disease are not well-understood. Here, we show that activation of Notch developmental signaling in estrogen receptor (ER)-negative breast cancer cells results in direct transcriptional up-regulation of the apoptosis inhibitor and cell cycle regulator survivin. This response is associated with increased expression of survivin at mitosis, enhanced cell proliferation, and heightened viability at cell division. Conversely, targeting Notch signaling with a peptidyl gamma-secretase inhibitor suppressed survivin levels, induced apoptosis, abolished colony formation in soft agar, and inhibited localized and metastatic tumor growth in mice, without organ or systemic toxicity. In contrast, ER+ breast cancer cells, or various normal cell types, were insensitive to Notch stimulation. Therefore, ER- breast cancer cells become dependent on Notch-survivin signaling for their maintenance, in vivo. Therapeutic targeting of this pathway may be explored for individualized treatment of patients with clinically aggressive, ER- breast cancer.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=18593928&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652573/
dc.subjectAdenocarcinoma
dc.subjectAmyloid Precursor Protein Secretases
dc.subjectAnimals
dc.subjectBreast Neoplasms
dc.subjectCell Proliferation
dc.subjectCell Survival
dc.subjectCells, Cultured
dc.subjectDrug Resistance, Neoplasm
dc.subjectEstrogen Receptor alpha
dc.subjectFemale
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectHela Cells
dc.subjectHumans
dc.subjectMice
dc.subjectMice, SCID
dc.subjectMicrotubule-Associated Proteins
dc.subjectNeoplasm Proteins
dc.subjectOligopeptides
dc.subjectProtease Inhibitors
dc.subjectReceptor, Notch1
dc.subjectReceptors, Notch
dc.subjectSignal Transduction
dc.subjectXenograft Model Antitumor Assays
dc.subjectLife Sciences
dc.subjectMedicine and Health Sciences
dc.titleMolecular dependence of estrogen receptor-negative breast cancer on a notch-survivin signaling axis
dc.typeArticle
dc.source.journaltitleCancer research
dc.source.volume68
dc.source.issue13
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/1963
dc.identifier.contextkey1053790
html.description.abstract<p>Despite progress in the management of breast cancer, the molecular underpinnings of clinically aggressive subtypes of the disease are not well-understood. Here, we show that activation of Notch developmental signaling in estrogen receptor (ER)-negative breast cancer cells results in direct transcriptional up-regulation of the apoptosis inhibitor and cell cycle regulator survivin. This response is associated with increased expression of survivin at mitosis, enhanced cell proliferation, and heightened viability at cell division. Conversely, targeting Notch signaling with a peptidyl gamma-secretase inhibitor suppressed survivin levels, induced apoptosis, abolished colony formation in soft agar, and inhibited localized and metastatic tumor growth in mice, without organ or systemic toxicity. In contrast, ER+ breast cancer cells, or various normal cell types, were insensitive to Notch stimulation. Therefore, ER- breast cancer cells become dependent on Notch-survivin signaling for their maintenance, in vivo. Therapeutic targeting of this pathway may be explored for individualized treatment of patients with clinically aggressive, ER- breast cancer.</p>
dc.identifier.submissionpathoapubs/1963
dc.contributor.departmentDepartment of Cancer Biology and the Cancer Center
dc.source.pages5273-81


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