DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer.
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.
Lott
Steven T
ST
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Chen
Nanyue
N
Chandler
Dawn S
DS
Yang
Qifeng
Q
Wang
Luo
L
Rodriguez
Marivonne
M
Xie
Hongyan
H
Balasenthil
Seetharaman
S
Buchholz
Thomas A
TA
Sahin
Aysegul A
AA
Chaung
Katrina
K
Zhang
Baili
B
Olufemi
Shodimu-Emmanu
SE
Chen
Jinyun
J
Adams
Henry
H
Band
Vimla
V
El-Naggar
Adel K
AK
Frazier
Marsha L
ML
Keyomarsi
Khandan
K
Hunt
Kelly K
KK
Sen
Subrata
S
Haffty
Bruce
B
Hewitt
Stephen M
SM
Krahe
Ralf
R
Killary
Ann McNeill
AM
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
D014408:Biomarkers, Tumor; D000070584:Tripartite Motif Proteins; D025521:Tumor Suppressor Proteins; C583162:TRIM62 protein, human; D044767:Ubiquitin-Protein Ligases