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

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Annals of Surgical Oncology Aims and scope Submit manuscript

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 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.

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Acknowledgements

We would like to acknowledge the contributions of David Shilling and Dr. Kathleen O’Sullivan for technical assistance and statistical analysis respectively.

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Authors and Affiliations

  1. Department of Academic Surgery, Cork University Hospital, Cork, Ireland

    Myles J. Smith MRCSI, PhD, Shane Killeen MRCSI, MD, Maura A. Kelly MRCSI, Jiang H. Wang PhD & Henry P. Redmond MCh, FRCSI

  2. Tumour Biology and Biochemistry, Cork University Hospital, University College Cork, Cork, Ireland

    Myles J. Smith MRCSI, PhD & Thomas G. Cotter D. Phil

  3. Department of Biostatistics, Harvard School of Public Health, Boston, MA, 02115, USA

    Aedín C. Culhane PhD

  4. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Aedín C. Culhane PhD

Authors
  1. Myles J. Smith MRCSI, PhD
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  2. Aedín C. Culhane PhD
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  3. Shane Killeen MRCSI, MD
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  4. Maura A. Kelly MRCSI
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  5. Jiang H. Wang PhD
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  6. Thomas G. Cotter D. Phil
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  7. Henry P. Redmond MCh, FRCSI
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Corresponding author

Correspondence to Myles J. Smith MRCSI, PhD.

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Smith, M.J., Culhane, A.C., Killeen, S. et al. Mechanisms Driving Local Breast Cancer Recurrence in a Model of Breast-Conserving Surgery. Ann Surg Oncol 15, 2954–2964 (2008). https://doi.org/10.1245/s10434-008-0037-5

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  • DOI: https://doi.org/10.1245/s10434-008-0037-5

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