Cell Death in MMTV-c-myc Transgenic Mouse Mammary Tumors May Not Be Typical Apoptosis

Dezhong Joshua Liao, Robert B. Dickson

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Enforced expression of c-myc has been shown to serve as an apoptotic stimulus in cultured cells. Prior studies have also demonstrated that several tissues expressing c-myc transgene display a large number of dead cells, although a morphologic or biochemical verification of apoptosis in these tissues has actually not been presented. In the present study, we examined the morphologic properties of cell death in the mammary tumors developed from MMTV-c-myc transgenic mice. We found that c-myc-expressing mammary tumor cells exhibited malformation of mitochondria, characterized by an amorphous matrix with very few cristae. The mitochondria were also frequently degenerated by lysis of the matrix and cristae. The protein level of cytochrome c was much lower in the areas of c-myc-expressing tumor cells compared with the adjacent tumor foci, which was previously shown to have decreased expression of c-myc, reduced frequencies of cell death, and increased frequencies of proliferating cells. In the c-myc-expressing tumor areas, there were many dying or dead cells organized in clusters, termed "dead cell islands." These cells exhibited shrinkage, DNA breakage as indicated by a positive TUNEL staining, and nuclear localization of apoptosis-inducing factor, but a lack of typical apoptotic morphology, such as nuclear condensation and formation of cell membrane blebs and apoptotic bodies. Many macrophages infiltrated into these dead cell islands, engulfing the dying or dead tumor cells. In the total tumor tissue, the protein level of caspase-3 was very low, and the poly(ADP)-ribose polymerase was present mainly as the unprocessed, inactive form. Collectively, these results suggest that programmed cell death in the c-myc transgenic mammary tumor tissue may not be typical apoptosis and may involve a caspase-independent mechanism.

Original languageEnglish (US)
Pages (from-to)1437-1449
Number of pages13
JournalLaboratory Investigation
Issue number10
StatePublished - Oct 2003
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by National Institues of Health grants RO1 CA72460 and AG1496 (to RBD), by Department of Defense grant DAMD17–00–1-0270 (to DJL and RBD), and by a DOD postdoctoral fellowship (to DJL). Address reprint requests to: Dr. Joshua Liao, HWCRC, Room 703, Kar-manos Cancer Institute and Department of Pathology, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, Michigan 48201. Email: dliao@med.wayne.edu


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