TY - JOUR
T1 - Postpartum breast involution reveals regression of secretory lobules mediated by tissue-remodeling
AU - Jindal, Sonali
AU - Gao, Dexiang
AU - Bell, Pat
AU - Albrektsen, Grethe
AU - Edgerton, Susan M.
AU - Ambrosone, Christine B.
AU - Thor, Ann D.
AU - Borges, Virginia F.
AU - Schedin, Pepper
N1 - Funding Information:
This work was supported by Department of Defense (grant numbers BC104000, BC10400P1) to PS and VB, National Institute of Health (1R01CA169175) to PS and VB, CCSG (grant number NIH P30 CA016056-27) and the Avon, Men for the Cure, Grohne Family and Glass Family-Foundations. The authors appreciate the contribution to this research from the Tissue Bio banking and Processing Shared Resource of Colorado’s NIH/NCI Cancer Center Support Grant P30CA046934. We acknowledge the Colorado CTSI (NIH/NCRR Grant Number UL1 RR025780) for the Redcap resource. We thank Elizabeth Manthey for support in the acquisition of clinical histories, and Dr. Lisa Hines and Adrie vanBokhoven for making human tissue available for this research. Samples from the Susan G. Komen Tissue Bank at the IU Simon Cancer Center were used in this study and we thank all participant involved. The histological slides from Norway would not been available without the comprehensive work related to location of tissue blocks, performed by Siri Larønningen at the Cancer Registry of Norway, and the willingness from 16 different pathological laboratories in Norway (located in Oslo, Bergen, Trondheim, Drammen, Fredrikstad, Kristiansand, Lillehammer, Lørenskog, Molde, Stavanger, Tromsø, Tønsberg and Ålesund), to contribute histological slides and tissue blocks. We are especially thankful to Ellen Hellesylt at the pathological clinic at the Radium hospital in Oslo, Norway, for preparation of histological slides. We appreciate Clarissa Durand-Rougely for assistance with Aperio nuclear counts and figure designs, Drs. Mark Sherman and Brandy Heckmann-Stoddard for assistance with morphometric analyses and stimulating discussion, Dr. Jennifer Richer and Dr. Margaret C. Neville for critical review of the manuscript, and members of Schedin-Borges lab for their intellectual contribution. Finally, we are very grateful to the patients for their contribution to this research.
PY - 2014/3/28
Y1 - 2014/3/28
N2 - Introduction: A postpartum diagnosis of breast cancer is an independent predictor of metastases, however the reason is unknown. In rodents, the window of postpartum mammary gland involution promotes tumor progression, suggesting a role for breast involution in the poor prognosis of human postpartum breast cancers. Rodent mammary gland involution is characterized by the programmed elimination of the secretory lobules laid down in preparation for lactation. This tissue involution process involves massive epithelial cell death, stromal remodeling, and immune cell infiltration with similarities to microenvironments present during wound healing and tumor progression. Here, we characterize breast tissue from premenopausal women with known reproductive histories to determine the extent, duration and cellular mechanisms of postpartum lobular involution in women.Methods: Adjacent normal breast tissues from premenopausal women (n = 183) aged 20 to 45 years, grouped by reproductive categories of nulliparous, pregnant and lactating, and by time since last delivery were evaluated histologically and by special stain for lobular area, lobular type composition, apoptosis and immune cell infiltration using computer assisted quantitative methods.Results: Human nulliparous glands were composed dominantly of small (approximately 10 acini per lobule) and medium (approximately 35 acini per lobule) sized lobules. With pregnancy and lactation, a >10 fold increase in breast epithelial area was observed compared to nulliparous cases, and lactating glands were dominated by mature lobules (>100 acini per lobule) with secretory morphology. Significant losses in mammary epithelial area and mature lobule phenotypes were observed within 12 months postpartum. By 18 months postpartum, lobular area content and lobule composition were indistinguishable from nulliparous cases, data consistent with postpartum involution facilitating regression of the secretory lobules developed in preparation for lactation. Analyses of apoptosis and immune cell infiltrate confirmed that human postpartum breast involution is characterized by wound healing-like tissue remodeling programs that occur within a narrowed time frame.Conclusions: Human postpartum breast involution is a dominant tissue-remodeling process that returns the total lobular area of the gland to a level essentially indistinguishable from the nulliparous gland. Further research is warranted to determine whether the normal physiologic process of postpartum involution contributes to the poor prognosis of postpartum breast cancer.
AB - Introduction: A postpartum diagnosis of breast cancer is an independent predictor of metastases, however the reason is unknown. In rodents, the window of postpartum mammary gland involution promotes tumor progression, suggesting a role for breast involution in the poor prognosis of human postpartum breast cancers. Rodent mammary gland involution is characterized by the programmed elimination of the secretory lobules laid down in preparation for lactation. This tissue involution process involves massive epithelial cell death, stromal remodeling, and immune cell infiltration with similarities to microenvironments present during wound healing and tumor progression. Here, we characterize breast tissue from premenopausal women with known reproductive histories to determine the extent, duration and cellular mechanisms of postpartum lobular involution in women.Methods: Adjacent normal breast tissues from premenopausal women (n = 183) aged 20 to 45 years, grouped by reproductive categories of nulliparous, pregnant and lactating, and by time since last delivery were evaluated histologically and by special stain for lobular area, lobular type composition, apoptosis and immune cell infiltration using computer assisted quantitative methods.Results: Human nulliparous glands were composed dominantly of small (approximately 10 acini per lobule) and medium (approximately 35 acini per lobule) sized lobules. With pregnancy and lactation, a >10 fold increase in breast epithelial area was observed compared to nulliparous cases, and lactating glands were dominated by mature lobules (>100 acini per lobule) with secretory morphology. Significant losses in mammary epithelial area and mature lobule phenotypes were observed within 12 months postpartum. By 18 months postpartum, lobular area content and lobule composition were indistinguishable from nulliparous cases, data consistent with postpartum involution facilitating regression of the secretory lobules developed in preparation for lactation. Analyses of apoptosis and immune cell infiltrate confirmed that human postpartum breast involution is characterized by wound healing-like tissue remodeling programs that occur within a narrowed time frame.Conclusions: Human postpartum breast involution is a dominant tissue-remodeling process that returns the total lobular area of the gland to a level essentially indistinguishable from the nulliparous gland. Further research is warranted to determine whether the normal physiologic process of postpartum involution contributes to the poor prognosis of postpartum breast cancer.
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U2 - 10.1186/bcr3633
DO - 10.1186/bcr3633
M3 - Article
C2 - 24678808
AN - SCOPUS:84899693434
SN - 1465-5411
VL - 16
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 2
M1 - R31
ER -