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Myoepithelial cell layer disruption and human breast cancer invasion
Breast Cancer Research volume 7, Article number: P3.06 (2005)
Human breast luminal epithelium and the stromal compartment are separated by a layer of myoepithelial (ME) cells and basement membrane, whose disruption is required for tumor invasion. Basement membrane degradation has been ascribed largely to an overproduction of proteases by the tumor and stromal cells. However, the causes and phenotypes of ME cell layer disruption and its contribution to the initiation of tumor invasion remain to be further explored.
Human ductal carcinoma in situ samples with ME disruption and microinvasion were sectioned and immunohistochemically stained with Ki-67, estrogen receptor (ER), leukocyte common antigen, and other biochemical markers.
A subset of pre-invasive and micro-invasive tumors contained focal disruptions in their ME cell layer. ER-negative cell clusters overlying a focally disrupted ME cell layer and the basement membrane showed a significantly higher proliferation rate than adjacent cells within the same duct. These disruptions were associated with histochemical and genetic alterations in the overlying tumor cells, including the loss of ER expression, a higher frequency of loss of heterozygosity, and a higher expression of cell cycle, angiogenesis, and invasion-related genes. Focal ME layer disruptions were, in general, associated with a higher rate of epithelial proliferation and leukocyte infiltration; however, a small fraction of these ER-negative cells lacked proliferation and differentiation markers resembling dormant cancer stem cells.
We propose a novel hypothesis that a localized death of ME cells and immunoreactions that accompany an external environmental insult or internal genetic alterations are triggering factors for ME layer disruptions, basement membrane degradation, and subsequent tumor progression and invasion. Inflammation may contribute to the death of focal ME cells. Putative dormant cancer stem cells may be partially responsible for tumor drug resistance and recurrence.
Man YG, Sang QX: The significance of focal myoepithelial cell layer disruptions in human breast tumor invasion: a paradigm shift from the 'protease-centered' hypothesis [review]. Exp Cell Res. 2004, 301: 103-118. 10.1016/j.yexcr.2004.08.037.
Man YG, Shen T, Sang QX, Berg PE, Schwartz AM: Cell clusters in a subset of in situ breast tumors show an unusual growth pattern: implications for invasion and metastasis. Cancer Detect Prevent. 2005,
Supported in part by Congressionally Directed Medical Research Program/DOD grants DAMD17-01-1-0129 and DAMD17-01-1-0130 to YGM, and by DAMD17-02-1-0238, NIH grant CA78646, and Florida State University grants to QXS.
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Man, Y., Sang, Q. Myoepithelial cell layer disruption and human breast cancer invasion. Breast Cancer Res 7, P3.06 (2005) doi:10.1186/bcr1128
- Estrogen Receptor
- Myoepithelial Cell
- Estrogen Receptor Expression
- High Proliferation Rate
- Luminal Epithelium