Mechanisms driving local breast cancer recurrence in a model of breast-conserving surgery.

Hdl Handle:
http://hdl.handle.net/10147/208895
Title:
Mechanisms driving local breast cancer recurrence in a model of breast-conserving surgery.
Authors:
Smith, Myles J; Culhane, Aedin C; Killeen, Shane; Kelly, Maura A; Wang, Jiang H; Cotter, Thomas G; Redmond, Henry P
Affiliation:
Department of Academic Surgery, Cork University Hospital, Cork, Ireland., mylessmith@hotmail.com
Citation:
Ann Surg Oncol. 2008 Oct;15(10):2954-64. Epub 2008 Jul 12.
Journal:
Annals of surgical oncology
Issue Date:
3-Feb-2012
URI:
http://hdl.handle.net/10147/208895
DOI:
10.1245/s10434-008-0037-5
PubMed ID:
18622646
Abstract:
OBJECTIVE: We aimed to identify mechanisms driving local recurrence in a model of breast-conserving surgery (BCS) for breast cancer. BACKGROUND: Breast cancer recurrence after BCS remains a clinically significant, but poorly understood problem. We have previously reported that recurrent colorectal tumours demonstrate altered growth dynamics, increased metastatic burden and resistance to apoptosis, mediated by upregulation of phosphoinositide-3-kinase/Akt (PI3K/Akt). We investigated whether similar characteristics were evident in a model of locally recurrent breast cancer. METHODS: Tumours were generated by orthotopic inoculation of 4T1 cells in two groups of female Balb/c mice and cytoreductive surgery performed when mean tumour size was above 150 mm(3). Local recurrence was observed and gene expression was examined using Affymetrix GeneChips in primary and recurrent tumours. Differential expression was confirmed with quantitative real-time polymerase chain reaction (qRT-PCR). Phosphorylation of Akt was assessed using Western immunoblotting. An ex vivo heat shock protein (HSP)-loaded dendritic cell vaccine was administered in the perioperative period. RESULTS: We observed a significant difference in the recurrent 4T1 tumour volume and growth rate (p < 0.05). Gene expression studies suggested roles for the PI3K/Akt system and local immunosuppression driving the altered growth kinetics. We demonstrated that perioperative vaccination with an ex vivo HSP-loaded dendritic cell vaccine abrogated recurrent tumour growth in vivo (p = 0.003 at day 15). CONCLUSION: Investigating therapies which target tumour survival pathways such as PI3K/Akt and boost immune surveillance in the perioperative period may be useful adjuncts to contemporary breast cancer treatment.
Language:
eng
MeSH:
Animals; Blotting, Western; Bone Marrow/metabolism; Breast Neoplasms/metabolism/*pathology/surgery; Cancer Vaccines/therapeutic use; Dendritic Cells/immunology/metabolism; *Disease Models, Animal; Female; Gene Expression Profiling; Heat-Shock Proteins/therapeutic use; Humans; Mice; Mice, Inbred BALB C; Neoplasm Recurrence, Local/*diagnosis/metabolism; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt/metabolism; RNA, Messenger/genetics/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Survival Rate; Tumor Cells, Cultured; Tumor Markers, Biological/genetics/metabolism
ISSN:
1534-4681 (Electronic); 1068-9265 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorSmith, Myles Jen_GB
dc.contributor.authorCulhane, Aedin Cen_GB
dc.contributor.authorKilleen, Shaneen_GB
dc.contributor.authorKelly, Maura Aen_GB
dc.contributor.authorWang, Jiang Hen_GB
dc.contributor.authorCotter, Thomas Gen_GB
dc.contributor.authorRedmond, Henry Pen_GB
dc.date.accessioned2012-02-03T15:06:43Z-
dc.date.available2012-02-03T15:06:43Z-
dc.date.issued2012-02-03T15:06:43Z-
dc.identifier.citationAnn Surg Oncol. 2008 Oct;15(10):2954-64. Epub 2008 Jul 12.en_GB
dc.identifier.issn1534-4681 (Electronic)en_GB
dc.identifier.issn1068-9265 (Linking)en_GB
dc.identifier.pmid18622646en_GB
dc.identifier.doi10.1245/s10434-008-0037-5en_GB
dc.identifier.urihttp://hdl.handle.net/10147/208895-
dc.description.abstractOBJECTIVE: We aimed to identify mechanisms driving local recurrence in a model of breast-conserving surgery (BCS) for breast cancer. BACKGROUND: Breast cancer recurrence after BCS remains a clinically significant, but poorly understood problem. We have previously reported that recurrent colorectal tumours demonstrate altered growth dynamics, increased metastatic burden and resistance to apoptosis, mediated by upregulation of phosphoinositide-3-kinase/Akt (PI3K/Akt). We investigated whether similar characteristics were evident in a model of locally recurrent breast cancer. METHODS: Tumours were generated by orthotopic inoculation of 4T1 cells in two groups of female Balb/c mice and cytoreductive surgery performed when mean tumour size was above 150 mm(3). Local recurrence was observed and gene expression was examined using Affymetrix GeneChips in primary and recurrent tumours. Differential expression was confirmed with quantitative real-time polymerase chain reaction (qRT-PCR). Phosphorylation of Akt was assessed using Western immunoblotting. An ex vivo heat shock protein (HSP)-loaded dendritic cell vaccine was administered in the perioperative period. RESULTS: We observed a significant difference in the recurrent 4T1 tumour volume and growth rate (p < 0.05). Gene expression studies suggested roles for the PI3K/Akt system and local immunosuppression driving the altered growth kinetics. We demonstrated that perioperative vaccination with an ex vivo HSP-loaded dendritic cell vaccine abrogated recurrent tumour growth in vivo (p = 0.003 at day 15). CONCLUSION: Investigating therapies which target tumour survival pathways such as PI3K/Akt and boost immune surveillance in the perioperative period may be useful adjuncts to contemporary breast cancer treatment.en_GB
dc.language.isoengen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshBlotting, Westernen_GB
dc.subject.meshBone Marrow/metabolismen_GB
dc.subject.meshBreast Neoplasms/metabolism/*pathology/surgeryen_GB
dc.subject.meshCancer Vaccines/therapeutic useen_GB
dc.subject.meshDendritic Cells/immunology/metabolismen_GB
dc.subject.mesh*Disease Models, Animalen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshGene Expression Profilingen_GB
dc.subject.meshHeat-Shock Proteins/therapeutic useen_GB
dc.subject.meshHumansen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMice, Inbred BALB Cen_GB
dc.subject.meshNeoplasm Recurrence, Local/*diagnosis/metabolismen_GB
dc.subject.meshOligonucleotide Array Sequence Analysisen_GB
dc.subject.meshPhosphatidylinositol 3-Kinases/metabolismen_GB
dc.subject.meshPhosphorylationen_GB
dc.subject.meshProto-Oncogene Proteins c-akt/metabolismen_GB
dc.subject.meshRNA, Messenger/genetics/metabolismen_GB
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_GB
dc.subject.meshSignal Transductionen_GB
dc.subject.meshSurvival Rateen_GB
dc.subject.meshTumor Cells, Cultureden_GB
dc.subject.meshTumor Markers, Biological/genetics/metabolismen_GB
dc.titleMechanisms driving local breast cancer recurrence in a model of breast-conserving surgery.en_GB
dc.contributor.departmentDepartment of Academic Surgery, Cork University Hospital, Cork, Ireland., mylessmith@hotmail.comen_GB
dc.identifier.journalAnnals of surgical oncologyen_GB
dc.description.provinceMunster-

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