title: Molecular profiling of human mammary gland links breast cancer risk to a p27(+) cell population with progenitor characteristics.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Sibgat
authors.initials: S
authors.lastname: Choudhury
authors.forename: Vanessa
authors.initials: V
authors.lastname: Almendro
authors.forename: Vanessa F
authors.initials: VF
authors.lastname: Merino
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Filipe C
authors.initials: FC
authors.lastname: Martins
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Fackler
authors.forename: Marina
authors.initials: M
authors.lastname: Bessarabova
authors.forename: Adam
authors.initials: A
authors.lastname: Kowalczyk
authors.forename: Thomas
authors.initials: T
authors.lastname: Conway
authors.forename: Bryan
authors.initials: B
authors.lastname: Beresford-Smith
authors.forename: Geoff
authors.initials: G
authors.lastname: Macintyre
authors.forename: Yu-Kang
authors.initials: YK
authors.lastname: Cheng
authors.forename: Zoila
authors.initials: Z
authors.lastname: Lopez-Bujanda
authors.forename: Antony
authors.initials: A
authors.lastname: Kaspi
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Judith
authors.initials: J
authors.lastname: Robens
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nikolskaya
authors.forename: Vilde D
authors.initials: VD
authors.lastname: Haakensen
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Schnitt
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Ethington
authors.forename: Laura
authors.initials: L
authors.lastname: Panos
authors.forename: Michael
authors.initials: M
authors.lastname: Grant
authors.forename: Jason
authors.initials: J
authors.lastname: Clark
authors.forename: William
authors.initials: W
authors.lastname: Herlihy
authors.forename: S Joyce
authors.initials: SJ
authors.lastname: Lin
authors.forename: Grace
authors.initials: G
authors.lastname: Chew
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
authors.forename: April
authors.initials: A
authors.lastname: Greene-Colozzi
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Gedge D
authors.initials: GD
authors.lastname: Rosson
authors.forename: Malcolm
authors.initials: M
authors.lastname: Pike
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nikolsky
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Blum
authors.forename: Alfred
authors.initials: A
authors.lastname: Au
authors.forename: E Shelley
authors.initials: ES
authors.lastname: Hwang
authors.forename: Rulla M
authors.initials: RM
authors.lastname: Tamimi
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.forename: Izhak
authors.initials: I
authors.lastname: Haviv
authors.forename: X Shirley
authors.initials: XS
authors.lastname: Liu
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D042361:Mammary Glands, Human / Q000166:cytology* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010298:Parity / Q000235:genetics*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D015415:Biomarkers; C436291:CDKN1B protein, human; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27