@article{05c81f7ed62d4afc9a30b8f300be662d,
title = "The luminal progenitor compartment of the normal human mammary gland constitutes a unique site of telomere dysfunction",
abstract = "Telomeres are essential for genomic integrity, but little is known about their regulation in the normal human mammary gland. We now demonstrate that a phenotypically defined cell population enriched in luminal progenitors (LPs) is characterized by unusually short telomeres independently of donor age. Furthermore, we find that multiple DNA damage response proteins colocalize with telomeres in >95% of LPs but in <5% of basal cells. Paradoxically, 25% of LPs are still capable of exhibiting robust clonogenic activity in vitro. This may be partially explained by the elevated telomerase activity that was also seen only in LPs. Interestingly, this potential telomere salvage mechanism declines with age. Our findings thus reveal marked differences in the telomere biology of different subsets of primitive normal human mammary cells. The chronically dysfunctional telomeres unique to LPs have potentially important implications for normal mammary tissue homeostasis as well as the development of certain breast cancers.",
author = "Nagarajan Kannan and Nazmul Huda and Liren Tu and Radina Droumeva and Geraldine Aubert and Elizabeth Chavez and Brinkman, {Ryan R.} and Peter Lansdorp and Joanne Emerman and Satoshi Abe and Connie Eaves and David Gilley",
note = "Funding Information: We thank A. Bates, D. Wilkinson, D. Ko, W. Xu, and A. Haegert for excellent technical assistance, and Drs. J. Sproul and N. Van Laeken for assistance in obtaining mammoplasty tissue. N.K. held a Canadian Breast Cancer Foundation Postdoctoral Fellowship. This work was supported by a grant to C.E. from the Canadian Breast Cancer Research Alliance funded by the Canadian Cancer Society, by grants to R.B. from the Terry Fox Research Institute and the Terry Fox Foundation, and by grants to D.G. from the Indiana University Cancer Center, the American Cancer Society, the Showalter Foundation, the Susan G. Komen Foundation, the Avon Foundation, the Flight Attendant Medical Research Institute, and the Indiana Genomics Initiative (INGEN). INGEN of Indiana University is supported in part by Lilly Endowment, Inc. N.K., N.H., C.E., and D.G. conceptualized and designed the study. N.K. isolated cells and RNA for most experiments and conducted progenitor assays. N.H. conducted most of the biochemical and imaging analysis and contributed to writing the manuscript. R.D. and R.B. contributed to microarray analysis. P.L., G.A., and E.C. generated the Flow-FISH and Q-FISH data. J.E. helped organize accrual of the mammoplasty tissue. L.T. and S.A. helped with biochemical studies and data presentation. N.K., C.E., and D.G. wrote the manuscript, which was then critiqued and approved by all authors. ",
year = "2013",
doi = "10.1016/j.stemcr.2013.04.003",
language = "English (US)",
volume = "1",
pages = "28--37",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "1",
}