Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation [electronic resource] : an agent-based model supported by in vitro studies

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Tác giả:

Ngôn ngữ: eng

Ký hiệu phân loại: 611.39 Human anatomy, cytology, histology

Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2010

Mô tả vật lý: Size: Article No. R11 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 261666

 Introduction: Most human mammary epithelial cells (HMEC) cultured from histologically normal breast tissues enter a senescent state termed stasis after 5 to 20 population doublings. These senescent cells display increased size, contain senescence associated b-galactosidase activity, and express cyclin-dependent kinase inhibitor, p16INK4A (CDKN2A
  p16). However, HMEC grown in a serum-free medium, spontaneously yield, at low frequency, variant (v) HMEC that are capable of long-term growth and are susceptible to genomic instability. We investigated whether ionizing radiation, which increases breast cancer risk in women, affects the rate of vHMEC outgrowth. Methods: Pre-stasis HMEC cultures were exposed to 5 to 200 cGy of sparsely (X- or g-rays) or densely (1 GeV/amu 56Fe) ionizing radiation. Proliferation (bromodeoxyuridine incorporation), senescence (senescence-associated b-galactosidase activity), and p16 expression were assayed in subcultured irradiated or unirradiated populations four to six weeks following radiation exposure, when patches of vHMEC became apparent. Long-term growth potential and p16 promoter methylation in subsequent passages were also monitored. Agent-based modeling, incorporating a simple set of rules and underlying assumptions, was used to simulate vHMEC outgrowth and evaluate mechanistic hypotheses. Results: Cultures derived from irradiated cells contained significantly more vHMEC, lacking senescence associated b-galactosidase or p16 expression, than cultures derived from unirradiated cells. As expected, post-stasis vHMEC cultures derived from both unirradiated and irradiated cells exhibited more extensive methylation of the p16 gene than pre-stasis HMEC cultures. However, the extent of methylation of individual CpG sites in vHMEC samples did not correlate with passage number or treatment. Exposure to sparsely or densely ionizing radiation elicited similar increases in the numbers of vHMEC compared to unirradiated controls. Agent-based modeling indicated that radiation-induced premature senescence of normal HMEC most likely accelerated vHMEC outgrowth through alleviation of spatial constraints. Subsequent experiments using defined co-cultures of vHMEC and senescent cells supported this mechanism. Conclusions: Our studies indicate that ionizing radiation can promote the outgrowth of epigenetically altered cells with pre-malignant potential
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