title: DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer.
abstract: BACKGROUND
  Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium-associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.
  
  
  RESULTS
  Suppression subtractive hybridization identified DEAR1 as a novel gene mapping to a region of high-frequency loss of heterozygosity (LOH) in a number of histologically diverse human cancers within Chromosome 1p35.1. In the breast epithelium, DEAR1 expression is limited to the ductal and glandular epithelium and is down-regulated in transition to ductal carcinoma in situ (DCIS), an early histologic stage in breast tumorigenesis. DEAR1 missense mutations and homozygous deletion (HD) were discovered in breast cancer cell lines and tumor samples. Introduction of the DEAR1 wild type and not the missense mutant alleles to complement a mutation in a breast cancer cell line, derived from a 36-year-old female with invasive breast cancer, initiated acinar morphogenesis in three-dimensional (3D) basement membrane culture and restored tissue architecture reminiscent of normal acinar structures in the mammary gland in vivo. Stable knockdown of DEAR1 in immortalized human mammary epithelial cells (HMECs) recapitulated the growth in 3D culture of breast cancer cell lines containing mutated DEAR1, in that shDEAR1 clones demonstrated disruption of tissue architecture, loss of apical basal polarity, diffuse apoptosis, and failure of lumen formation. Furthermore, immunohistochemical staining of a tissue microarray from a cohort of 123 young female breast cancer patients with a 20-year follow-up indicated that in early-onset breast cancer, DEAR1 expression serves as an independent predictor of local recurrence-free survival and correlates significantly with strong family history of breast cancer and the triple-negative phenotype (ER(-), PR(-), HER-2(-)) of breast cancers with poor prognosis.
  
  
  CONCLUSIONS
  Our data provide compelling evidence for the genetic alteration and loss of expression of DEAR1 in breast cancer, for the functional role of DEAR1 in the dominant regulation of acinar morphogenesis in 3D culture, and for the potential utility of an immunohistochemical assay for DEAR1 expression as an independent prognostic marker for stratification of early-onset disease.
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Lott
authors.forename: Nanyue
authors.initials: N
authors.lastname: Chen
authors.forename: Dawn S
authors.initials: DS
authors.lastname: Chandler
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Yang
authors.forename: Luo
authors.initials: L
authors.lastname: Wang
authors.forename: Marivonne
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Hongyan
authors.initials: H
authors.lastname: Xie
authors.forename: Seetharaman
authors.initials: S
authors.lastname: Balasenthil
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchholz
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.forename: Katrina
authors.initials: K
authors.lastname: Chaung
authors.forename: Baili
authors.initials: B
authors.lastname: Zhang
authors.forename: Shodimu-Emmanu
authors.initials: SE
authors.lastname: Olufemi
authors.forename: Jinyun
authors.initials: J
authors.lastname: Chen
authors.forename: Henry
authors.initials: H
authors.lastname: Adams
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.forename: Subrata
authors.initials: S
authors.lastname: Sen
authors.forename: Bruce
authors.initials: B
authors.lastname: Haffty
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Ralf
authors.initials: R
authors.lastname: Krahe
authors.forename: Ann McNeill
authors.initials: AM
authors.lastname: Killary
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001940:Breast / Q000254:growth & development* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D015536:Down-Regulation / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D009024:Morphogenesis / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics; D011379:Prognosis; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D044767:Ubiquitin-Protein Ligases
chemical_list: D014408:Biomarkers, Tumor; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins; C583162:TRIM62 protein, human; D044767:Ubiquitin-Protein Ligases