Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment

K. K C Tsai, Yao Yu Eric Chuang, John B. Little, Zhi Min Yuan

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Radiation exposure is an important form of environmental carcinogen and has been associated with increased risk of breast cancer. Epigenetic events, especially those involving alterations in the breast stromal microenvironment, may play an important role in radiation-induced carcinogenesis but remain not well understood. We here show that human mammary stromal fibroblasts respond to protracted low-dose ionizing radiation exposures by displaying a senescence-like phenotype. Using a three-dimensional coculture system to model the interactions of different mammary cell types with their neighbors and with their environment, we provide a direct experimental proof that ionizing radiation-induced senescence-like fibroblasts significantly perturb the mammary stromal microenvironment, which is highlighted by impaired formation of pseudopodia networks due to marked cytoskeletal alterations in senescence-like fibroblasts and increased extracellular matrix degradation because of the up-regulation of multiple secreted matrix metalloproteinases. Within such a perturbed environment, mammary ductal morphogenesis is completely disrupted and epithelial cells instead grow into enlarged cystic structures, which further develop and become disorganized cell masses on inactivation of cellular death pathways. Breast carcinoma cells growing in such an environment are enabled to fully express their malignant potential as evidenced by the α6β4 integrin/phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway-dependent invasive growth. Our results suggest that ionizing radiation, in addition to causing gene mutations in epithelial cells, can contribute to breast carcinogenesis by perturbing the tissue microenvironment that leads to dysregulated cell-cell and cell-matrix interactions.

Original languageEnglish
Pages (from-to)6734-6744
Number of pages11
JournalCancer Research
Volume65
Issue number15
DOIs
Publication statusPublished - Aug 1 2005
Externally publishedYes

Fingerprint

Ionizing Radiation
Breast
Fibroblasts
Secreted Matrix Metalloproteinases
Carcinogenesis
Epithelial Cells
Phosphatidylinositol 3-Kinase
Environmental Carcinogens
Breast Neoplasms
Pseudopodia
Sirolimus
Coculture Techniques
Morphogenesis
Epigenomics
Integrins
Cell Communication
Extracellular Matrix
Up-Regulation
Radiation
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. / Tsai, K. K C; Chuang, Yao Yu Eric; Little, John B.; Yuan, Zhi Min.

In: Cancer Research, Vol. 65, No. 15, 01.08.2005, p. 6734-6744.

Research output: Contribution to journalArticle

Tsai, K. K C ; Chuang, Yao Yu Eric ; Little, John B. ; Yuan, Zhi Min. / Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. In: Cancer Research. 2005 ; Vol. 65, No. 15. pp. 6734-6744.
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