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10.1245/s10434-008-0037-5
Annals of Surgical Oncology 15:2954-2964 (2008)
© 2008 Society of Surgical Oncology
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Original Article

Mechanisms Driving Local Breast Cancer Recurrence in a Model of Breast-Conserving Surgery

Myles J. Smith, MRCSI, PhD1,2, Aedín C. Culhane, PhD3,4, Shane Killeen, MRCSI, MD1, Maura A. Kelly, MRCSI1, Jiang H. Wang, PhD1, Thomas G. Cotter, D.Phil2 and Henry P. Redmond, MCh, FRCSI1

1 Department of Academic Surgery, Cork University Hospital, Cork, Ireland
2 Tumour Biology and Biochemistry, Cork University Hospital, University College Cork, Cork, Ireland
3 Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA
4 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA

Correspondence: Address correspondence and reprint requests to: Myles J. Smith, MRCSI, PhD; E-mail: mylessmith{at}hotmail.com

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 mm3. 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.

Key Words: Breast cancer • Local recurrence • Animal model • Microarray • Vaccine






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