WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells.
Recent studies have identified a subpopulation of highly tumorigenic cells with stem/progenitor cell properties from human breast cancers, and it has been suggested that stem/progenitor cells, which remain after breast cancer therapy, may give rise to recurrent disease. We hypothesized that progenitor cells are resistant to radiation, a component of conventional breast cancer therapy, and that that resistance is mediated at least in part by Wnt signaling, which has been implicated in stem cell survival. To test this hypothesis, we investigated radioresistance by treating primary BALB/c mouse mammary epithelial cells with clinically relevant doses of radiation and found enrichment in normal progenitor cells (stem cell antigen 1-positive and side population progenitors). Radiation selectively enriched for progenitors in mammary epithelial cells isolated from transgenic mice with activated Wnt/beta-catenin signaling but not for background-matched controls, and irradiated stem cell antigen 1-positive cells had a selective increase in active beta-catenin and survivin expression compared with stem cell antigen 1-negative cells. In clonogenic assays, colony formation in the stem cell antigen 1-positive progenitors was unaffected by clinically relevant doses of radiation. Radiation also induced enrichment of side population progenitors in the human breast cancer cell line MCF-7. These data demonstrate that, compared with differentiated cells, progenitor cells have different cell survival properties that may facilitate the development of targeted antiprogenitor cell therapies.
Woodward
Wendy A
WA
Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Chen
Mercy S
MS
Behbod
Fariba
F
Alfaro
Maria P
MP
Buchholz
Thomas A
TA
Rosen
Jeffrey M
JM
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051034:Inhibitor of Apoptosis Proteins; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000528:radiation effects; D011836:Radiation Tolerance / Q000502:physiology*; D012097:Repressor Proteins; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000528:radiation effects; D000077022:Survivin; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
C117749:Birc5 protein, mouse; C495267:CTNNB1 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D000077022:Survivin; D051153:Wnt Proteins; D051176:beta Catenin