Comedo-ductal carcinoma in situ

A paradoxical role for programmed cell death

Malathy P V Shekhar, Larry Tait, Robert J. Pauley, Gen Sheng Wu, Steven J. Santner, Pratima Nangia-Makker, Varun Shekhar, Hind Nassar, Daniel W Visscher, Gloria H. Heppner, Fred R. Miller

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Comedo-DCIS is a histologic subtype of preinvasive breast neoplasia that is characterized by prominent apoptotic cell death and has greater malignant potential than other DCIS subtypes. We investigated the mechanisms of apoptosis in comedo-DCIS and its role in conversion of comedo-DCIS to invasive cancer. Clinical comedo-DCIS excisions, and the MCF10DCIS.com human breast cancer model which produces lesions resembling comedo-DCIS were analyzed. Apoptotic luminal and myoepithelial cells were identified by TUNEL and reactivity to cleaved PARP antibody, and cell death assessed by Western blotting, Mitocapture, and immunohistochemical assays. MCF10DCIS.com cells undergo spontaneous apoptosis in vitro, both in monolayers and multicellular spheroids; it is associated with increased mitochondrial membrane permeability, increase in Bax/Bcl-2 ratio, and occurs via caspase-9-dependent p53-independent pathway. This suggests that apoptosis is stromal-independent and that the cells are programmed to undergo apoptosis. Immunostaining with cleaved PARP antibody showed that myoepithelial apoptosis occurs before lesions progress to comedo-DCIS in both clinical comedo-DCIS and in vivo MCF10DCIS.com lesions. Intense staining for MMP-2, MMP-3, MMP-9, and MMP-11 was observed in the stroma and epithelia of solid DCIS lesions prior to conversion to comedo-DCIS in clinical and MCF10DCIS.com lesions. Gelatin zymography showed higher MMP-2 levels in lysates and conditioned media of MCF10DCIS. com cells undergoing apoptosis. These data suggest that signals arising from the outside (microenvironmental) and inside (internal genetic alterations) of the duct act in concert to trigger apoptosis of myoepithelial and luminal epithelial cells. Our findings implicate spontaneous apoptosis in both the etiology and progression of comedo-DCIS. It is possible that spontaneous apoptosis facilitates elimination of cells thus permitting expansion and malignant transformation of cancer cells that are resistant to spontaneous apoptosis.

Original languageEnglish (US)
Pages (from-to)1774-1782
Number of pages9
JournalCancer Biology and Therapy
Volume7
Issue number11
StatePublished - Nov 2008
Externally publishedYes

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Carcinoma, Intraductal, Noninfiltrating
Cell Death
Apoptosis
Matrix Metalloproteinases
Cellular Spheroids
Neoplasms
Caspase 9
Antibodies
In Situ Nick-End Labeling
Mitochondrial Membranes
Gelatin
Stromal Cells
Conditioned Culture Medium
Permeability
Breast
Epithelium
Western Blotting
Epithelial Cells
Staining and Labeling
Breast Neoplasms

Keywords

  • Gelatin zymography
  • Matrix metalloproteinases
  • Mitochondria
  • Spontaneous apoptosis
  • TUNEL

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Shekhar, M. P. V., Tait, L., Pauley, R. J., Wu, G. S., Santner, S. J., Nangia-Makker, P., ... Miller, F. R. (2008). Comedo-ductal carcinoma in situ: A paradoxical role for programmed cell death. Cancer Biology and Therapy, 7(11), 1774-1782.

Comedo-ductal carcinoma in situ : A paradoxical role for programmed cell death. / Shekhar, Malathy P V; Tait, Larry; Pauley, Robert J.; Wu, Gen Sheng; Santner, Steven J.; Nangia-Makker, Pratima; Shekhar, Varun; Nassar, Hind; Visscher, Daniel W; Heppner, Gloria H.; Miller, Fred R.

In: Cancer Biology and Therapy, Vol. 7, No. 11, 11.2008, p. 1774-1782.

Research output: Contribution to journalArticle

Shekhar, MPV, Tait, L, Pauley, RJ, Wu, GS, Santner, SJ, Nangia-Makker, P, Shekhar, V, Nassar, H, Visscher, DW, Heppner, GH & Miller, FR 2008, 'Comedo-ductal carcinoma in situ: A paradoxical role for programmed cell death', Cancer Biology and Therapy, vol. 7, no. 11, pp. 1774-1782.
Shekhar MPV, Tait L, Pauley RJ, Wu GS, Santner SJ, Nangia-Makker P et al. Comedo-ductal carcinoma in situ: A paradoxical role for programmed cell death. Cancer Biology and Therapy. 2008 Nov;7(11):1774-1782.
Shekhar, Malathy P V ; Tait, Larry ; Pauley, Robert J. ; Wu, Gen Sheng ; Santner, Steven J. ; Nangia-Makker, Pratima ; Shekhar, Varun ; Nassar, Hind ; Visscher, Daniel W ; Heppner, Gloria H. ; Miller, Fred R. / Comedo-ductal carcinoma in situ : A paradoxical role for programmed cell death. In: Cancer Biology and Therapy. 2008 ; Vol. 7, No. 11. pp. 1774-1782.
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