Association of radiotherapy with preferential depletion of luminal epithelial cells in a BRCA1 mutation carrier
Radiation therapy (RT) after breast conservation therapy has recently been linked with significant reduction in risk of ipsilateral breast cancer among BRCA1 mutation carriers. However, the exact mechanism by which RT reduces incidence of BRCA1-associated cancer remains unclear. Here we studied fresh breast tissue from a BRCA1 mutation carrier who was initially treated with a lumpectomy and RT for a unilateral cancer and two years later chose a prophylactic bilateral mastectomy while remaining cancer-free. Flow cytometry analysis demonstrated a strikingly lower luminal cell population in the irradiated breast as compared to the non-irradiated breast, which was confirmed by immunohistochemistry. Furthermore, the irradiated breast tissue exhibited very low progenitor cell activity in vitro. Given the emerging evidence that BRCA1 tumors originate from luminal progenitor cells, our observations suggest that preferential and long-lasting elimination of luminal ductal epithelium may partly underlie the mechanism of RT-associated reduction in recurrence of BRCA1-associated cancer.
- Narod SA, Foulkes WD: BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 2004, 4:665–676. CrossRef
- Rosen EM, Fan S, Pestell RG, Goldberg ID: BRCA1 gene in breast cancer. J Cell Physiol 2003, 196:19–41. CrossRef
- Metcalfe K, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, Olopade OI, Domchek S, Eisen A, Foulkes WD, Rosen B, Vesprini D, Sun P, Narod SA: Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2011, 127:287–296. CrossRef
- Holland R, Veling SHJ, Mravunac M, Hendriks JHCL: Histologic multifocality of tis, T1–2 breast carcinomas implications for clinical trials of breast-conserving surgery. Cancer 1985, 56:979–990. CrossRef
- Holland R, Connolly JL, Gelman R, Mravunac M, Hendriks JH, Verbeek AL, Schnitt SJ, Silver B, Boyages J, Harris JR: The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast. J Clin Oncol 1990, 8:113–118.
- Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ: Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 2009, 15:907–913. CrossRef
- Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R, Mackay A, Grigoriadis A, Tutt A, Ashworth A, Reis-Filho JS, Smalley MJ: BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 2010, 7:403–417. CrossRef
- Proia TA, Keller PJ, Gupta PB, Klebba I, Jones AD, Sedic M, Gilmore H, Tung N, Naber SP, Schnitt S, Lander ES, Kuperwasser C: Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. Cell Stem Cell 2011, 8:149–163. CrossRef
- Murphy CG, Moynahan ME: BRCA gene structure and function in tumor suppression: a repair-centric perspective. Cancer J 2010, 16:39–47. CrossRef
- O'Donovan PJ, Livingston DM: BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis 2010, 31:961–967. CrossRef
- Eirew P, Stingl J, Raouf A, Turashvili G, Aparicio S, Emerman JT, Eaves CJ: A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability. Nat Med. 2008, 14:1384–1389. CrossRef
- Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, Li HI, Eaves CJ: Purification and unique properties of mammary epithelial stem cells. Nature 2006, 439:993–997.
- Stingl J, Eaves CJ, Zandieh I, Emerman JT: Characterization of bipotent mammary epithelial progenitor cells in normal adult human breast tissue. Breast Cancer Res Treat 2001, 67:93–109. CrossRef
- Stingl J: Detection and analysis of mammary gland stem cells. J Pathol 2009, 217:229–241. CrossRef
- Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, Godwin J, Gray R, Hicks C, James S, MacKinnon E, McGale P, McHugh T, Peto R, Taylor C, Wang Y: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005, 366:2087–2106.
- Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, Cutter D, Davies C, Ewertz M, Godwin J, Gray R, Pierce L, Whelan T, Wang Y, Peto R: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011, 378:1707–1716. CrossRef
- Brenner DJ, Shuryak I, Russo S, Sachs RK: Reducing second breast cancers: a potential role for prophylactic mammary irradiation. J Clin Oncol 2007, 25:4868–4872. CrossRef
- Association of radiotherapy with preferential depletion of luminal epithelial cells in a BRCA1 mutation carrier
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- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Experimental Hematology & Oncology
- Online Date
- October 2012
- Online ISSN
- BioMed Central
- Additional Links
- Author Affiliations
- 1. Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78245, USA
- 2. Department of Medicine, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78245, USA