Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment.
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 alpha6beta4 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.
Tsai
Kelvin K C
KK
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Chuang
Eric Yao-Yu
EY
Little
John B
JB
Yuan
Zhi-Min
ZM
D000818:Animals; D001940:Breast / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects*; D001943:Breast Neoplasms / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000528:radiation effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000528:radiation effects; D005109:Extracellular Matrix / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000209:etiology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017154:Stromal Cells / Q000166:cytology / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases
D020782:Matrix Metalloproteinases; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat