title: The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women.
abstract: The frequency and proliferative activity of tissue-specific stem and progenitor cells are suggested to correlate with cancer risk. In this study, we investigated the association between breast cancer risk and the frequency of mammary epithelial cells expressing p27, estrogen receptor (ER), and Ki67 in normal breast tissue. We performed a nested case-control study of 302 women (69 breast cancer cases, 233 controls) who had been initially diagnosed with benign breast disease according to the Nurses' Health Studies. Immunofluorescence for p27, ER, and Ki67 was performed on tissue microarrays constructed from benign biopsies containing normal mammary epithelium and scored by computational image analysis. We found that the frequency of Ki67(+) cells was positively associated with breast cancer risk among premenopausal women [OR = 10.1, 95% confidence interval (CI) = 2.12-48.0]. Conversely, the frequency of ER(+) or p27(+) cells was inversely, but not significantly, associated with subsequent breast cancer risk (ER(+): OR = 0.70, 95% CI, 0.33-1.50; p27(+): OR = 0.89, 95% CI, 0.45-1.75). Notably, high Ki67(+)/low p27(+) and high Ki67(+)/low ER(+) cell frequencies were significantly associated with a 5-fold higher risk of breast cancer compared with low Ki67(+)/low p27(+) and low Ki67(+)/low ER(+) cell frequencies, respectively, among premenopausal women (Ki67(hi)/p27(lo): OR = 5.08, 95% CI, 1.43-18.1; Ki67(hi)/ER(lo): OR = 4.68, 95% CI, 1.63-13.5). Taken together, our data suggest that the fraction of actively cycling cells in normal breast tissue may represent a marker for breast cancer risk assessment, which may therefore impact the frequency of screening procedures in at-risk women. Cancer Res; 76(7); 1926-34. ©2016 AACR.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Huh
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Hannah
authors.initials: H
authors.lastname: Oh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Peterson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Almendro
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Michaela
authors.initials: M
authors.lastname: Bowden
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rosina L
authors.initials: RL
authors.lastname: Lis
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Maura B
authors.initials: MB
authors.lastname: Cotter
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts. Harvard Stem Cell Institute, Cambridge, Massachusetts. Kornelia_Polyak@dfci.harvard.edu rulla.tamimi@channing.harvard.edu.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.affiliation: Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts. Kornelia_Polyak@dfci.harvard.edu rulla.tamimi@channing.harvard.edu.
authors.forename: Rulla M
authors.initials: RM
authors.lastname: Tamimi
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000209:etiology* / Q000473:pathology; D016022:Case-Control Studies; D004847:Epithelial Cells / Q000473:pathology*; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000473:pathology*; D017697:Premenopause