This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Parton, M. Articles by Dowsett, M. Search for Related Content PubMed PubMed Citation Articles by Parton, M. Articles by Dowsett, M.

Coordinate Expression of Apoptosis-associated Proteins in Human Breast Cancer before and during Chemotherapy¹

Breast Unit, Royal Marsden NHS Trust and Institute of Cancer Research, London SW3 6JJ, United Kingdom [M. P., I. S., C. A., R. A., M. D.]; The Burnham Institute, La Jolla, California 92037 [S. K., M. K., J. R.]; and University of Tokyo, Tokyo 113-0032, Japan [M. N.]

Purpose: Induction of apoptosis is a key factor in the response of tumors to chemotherapy. Laboratory studies have established many of the factors that regulate and execute apoptosis, but the significance of these in human tumors is poorly understood. Therefore, the relationship between key components of this machinery was examined in primary human breast carcinomas before and 24 h after the initiation of chemotherapy.

Experimental Design: Apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated nick end labeling assay, and proliferation was assessed using the anti-Ki67 antibody MIB-1. Monospecific polyclonal antibodies were used for immunohistochemical detection of Bcl-2, Bax, XIAP, activated (cleaved) caspase 3 and 6, and cleaved DNA Fragmentation Factor-40 (DFF40) using paraffin-embedded tissues.

Results: Before treatment, a significant correlation was found between apoptosis and proliferation (r = 0.64, P < 0.0001), between caspases 3 and 6 (r = 0.49, P = 0.004) and between cleaved DFF40 and active caspases 3 (r = 0.66, P < 0.0001) or 6 (r = 0.47, P = 0.006). Before treatment, expression of inhibitor of apoptosis protein, XIAP, also correlated positively with cleaved caspase 3 (r = 0.64, P < 0.0001), caspase 6 (r = 0.36, P = 0.04), and DFF40 (r = 0.61, P = 0.0001). At 24 h after chemotherapy, significant increases in apoptosis and decreases in proliferation were observed, with the degree of increase in apoptosis inversely associated with decrease in proliferation. Chemotherapy-induced increases in Bax were correlated with increases in cleaved DFF40 (r = 0.54, P = 0.0008), but no other variables showed significant change at 24 h after initiation of chemotherapy.

Conclusion: The pretreatment biomarker relationships suggest parallel cleavage and activation of these executioner proteins in breast cancer and that XIAP may maintain cell survival in the face of caspase activation. The findings provide in vivo evidence in human breast cancer that chemotherapy induces an apoptotic program characterized by up-regulation of Bax and cleavage of caspase substrate DFF40.

This article has been cited by other articles:

				F. Vegran, R. Boidot, C. Oudin, J.-M. Riedinger, F. Bonnetain, and S. Lizard-Nacol Overexpression of caspase-3s splice variant in locally advanced breast carcinoma is associated with poor response to neoadjuvant chemotherapy. Clin. Cancer Res., October 1, 2006; 12(19): 5794 - 5800. [Abstract] [Full Text] [PDF]

				H. H. Cheung, E. C. LaCasse, and R. G. Korneluk X-linked inhibitor of apoptosis antagonism: strategies in cancer treatment. Clin. Cancer Res., June 1, 2006; 12(11): 3238 - 3242. [Full Text] [PDF]

				H. Takeuchi, J. Kim, A. Fujimoto, N. Umetani, T. Mori, A. Bilchik, R. Turner, A. Tran, C. Kuo, and D. S.B. Hoon X-Linked Inhibitor of Apoptosis Protein Expression Level in Colorectal Cancer Is Regulated by Hepatocyte Growth Factor/C-Met Pathway via Akt Signaling Clin. Cancer Res., November 1, 2005; 11(21): 7621 - 7628. [Abstract] [Full Text] [PDF]

				A. Urruticoechea, I. E. Smith, and M. Dowsett Proliferation Marker Ki-67 in Early Breast Cancer J. Clin. Oncol., October 1, 2005; 23(28): 7212 - 7220. [Abstract] [Full Text] [PDF]

				O. Modlich, H.-B. Prisack, M. Munnes, W. Audretsch, and H. Bojar Immediate Gene Expression Changes After the First Course of Neoadjuvant Chemotherapy in Patients with Primary Breast Cancer Disease Clin. Cancer Res., October 1, 2004; 10(19): 6418 - 6431. [Abstract] [Full Text] [PDF]

				E. Floyd and T. M. Mcshane Development and Use of Biomarkers in Oncology Drug Development Toxicol Pathol, January 1, 2004; 32(1_suppl): 106 - 115. [Abstract] [PDF]

				L. Yang, Z. Cao, H. Yan, and W. C. Wood Coexistence of High Levels of Apoptotic Signaling and Inhibitor of Apoptosis Proteins in Human Tumor Cells: Implication for Cancer Specific Therapy Cancer Res., October 15, 2003; 63(20): 6815 - 6824. [Abstract] [Full Text] [PDF]

				N. O'Donovan, J. Crown, H. Stunell, A. D. K. Hill, E. McDermott, N. O'Higgins, and M. J. Duffy Caspase 3 in Breast Cancer Clin. Cancer Res., February 1, 2003; 9(2): 738 - 742. [Abstract] [Full Text] [PDF]