Molecular profiling of human mammary gland links breast cancer risk to a p27+ cell population with progenitor characteristics

Sibgat Choudhury, Vanessa Almendro, Vanessa F. Merino, Zhenhua Wu, Reo Maruyama, Ying Su, Filipe C. Martins, Mary Jo Fackler, Marina Bessarabova, Adam Kowalczyk, Thomas Conway, Bryan Beresford-Smith, Geoff Macintyre, Yu Kang Cheng, Zoila Lopez-Bujanda, Antony Kaspi, Rong Hu, Judith Robens, Tatiana Nikolskaya, Vilde D. HaakensenStuart J. Schnitt, Pedram Argani, Gabrielle Ethington, Laura Panos, Michael Grant, Jason Clark, William Herlihy, S. Joyce Lin, Grace Chew, Erik W. Thompson, April Greene-Colozzi, Andrea L. Richardson, Gedge D. Rosson, Malcolm Pike, Judy E. Garber, Yuri Nikolsky, Joanne L. Blum, Alfred Au, E. Shelley Hwang, Rulla M. Tamimi, Franziska Michor, Izhak Haviv, X. Shirley Liu, Saraswati Sukumar, Kornelia Polyak

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44+ progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell-cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44+p27+ cells in parous women and showed, using explant cultures, that parity-related signaling pathways play a role in regulating the number of p27+ cells and their proliferation. Our results suggest that pathways controlling p27+ mammary epithelial cells and the numbers of these cells relate to breast cancer risk and can be explored for cancer risk assessment and prevention. 2013

Original languageEnglish
Pages (from-to)117-130
Number of pages14
JournalCell Stem Cell
Issue number1
StatePublished - 3 Jul 2013
Externally publishedYes

Bibliographical note

Funding Information:
We thank Lisa Cameron in the DFCI Confocal and Light Microscopy Core Facility, members of Dr. Massimo Loda’s lab for technical assistance, members of our laboratories and Drs. Elgene Lim and David Livingston for their critical reading of this manuscript, Jonathan Yingling (Eli Lilly) for providing the LY2109761 TGF-β receptor kinase inhibitor, Drs. Sally Knox, Jeffrey Lamont, and Dao Tuoc (Baylor University Medical Center-Baylor Sammons Cancer Center), Erin Bowlby (University of California San Francisco, San Francisco), and Drs. Eli Golomg and Pikarski (Hadassah Medical Centre) for their help with collecting tissue samples from patients with BRCA1/BRCA2 germline mutation. Samples from the Susan G. Komen for the Cure Tissue Bank at the IU Simon Cancer Center were used in this study. We thank contributors, including Indiana University who collected samples used in this study, as well as donors and their families, whose help and participation made this work possible. This work was supported by the Avon Foundation (to K.P. and S.S.), the National Cancer Institute P50 CA89383 and P01 CA080111 (to S.J.S., K.P., and A.L.R.), CA116235-04S1 (to K.P.), and CA087969 (to R.M.T.), the Susan G. Komen Foundation (to R.M., Y.S., I.H., J.E.G., and K.P.), the Terri Brodeur Foundation (to S.C.), US Army Congressionally Directed Research W81XWH-07-1-0294 (to K.P.), the Victorian Breast Cancer Research Consortium (to S.J.L., G.C., and E.W.T.), the St. Vincent’s Hospital Research Endowment Fund and the Victorian Government’s OIS Program (to E.W.T.), the Programme for Advanced Medical Education funded by Fundação Calouste Gulbenkian (to F.M.), and the Cellex Foundation (to V.A.).


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