Abstract
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 language | English |
|---|---|
| Pages (from-to) | 117-130 |
| Number of pages | 14 |
| Journal | Cell Stem Cell |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| State | Published - 3 Jul 2013 |
| Externally published | Yes |
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.).
Funding
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.).
| Funders | Funder number |
|---|---|
| St. Vincent’s Hospital Research Endowment Fund | |
| National Cancer Institute | CA087969, P01CA080111, CA116235-04S1, P50 CA89383 |
| Congressionally Directed Medical Research Programs | W81XWH-07-1-0294 |
| Avon Foundation for Women | |
| Fundación Cellex | |
| Susan G. Komen | |
| Terri Brodeur Breast Cancer Foundation | |
| Translational Breast Cancer Research Consortium | |
| State Government of Victoria | |
| Fundação Calouste Gulbenkian |
