DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer

Steven T. Lott, Nanyue Chen, Dawn S. Chandler, Qifeng Yang, Luo Wang, Marivonne Rodriguez, Hongyan Xie, Seetharaman Balasenthil, Thomas A. Buchholz, Aysegul A. Sahin, Katrina Chaung, Baili Zhang, Shodimu Emmanu Olufemi, Jinyun Chen, Henry Adams, Vimla Band, Adel K. El-Naggar, Marsha L. Frazier, Khandan Keyomarsi, Kelly K. Hunt & 5 others Subrata Sen, Bruce Haffty, Stephen M. Hewitt, Ralf Krahe, Ann McNeill Killary

Research output: Contribution to journalArticle

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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. Methods and Findings: 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 (ER2, PR2, HER-22) 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.

Original languageEnglish (US)
Article numbere1000068
JournalPLoS medicine
Volume6
Issue number5
DOIs
StatePublished - May 1 2009

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Chromosomes, Human, Pair 1
Morphogenesis
Epithelium
Breast Neoplasms
Recurrence
Survival
Breast
Human Mammary Glands
RING Finger Domains
Triple Negative Breast Neoplasms
Cell Line
Carcinoma, Intraductal, Noninfiltrating
Loss of Heterozygosity
Chromosome Mapping
Missense Mutation
Tumor Cell Line
Basement Membrane
Carcinogenesis
Clone Cells
Chromosomes

ASJC Scopus subject areas

  • Medicine(all)

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DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer. / Lott, Steven T.; Chen, Nanyue; Chandler, Dawn S.; Yang, Qifeng; Wang, Luo; Rodriguez, Marivonne; Xie, Hongyan; Balasenthil, Seetharaman; Buchholz, Thomas A.; Sahin, Aysegul A.; Chaung, Katrina; Zhang, Baili; Olufemi, Shodimu Emmanu; Chen, Jinyun; Adams, Henry; Band, Vimla; El-Naggar, Adel K.; Frazier, Marsha L.; Keyomarsi, Khandan; Hunt, Kelly K.; Sen, Subrata; Haffty, Bruce; Hewitt, Stephen M.; Krahe, Ralf; Killary, Ann McNeill.

In: PLoS medicine, Vol. 6, No. 5, e1000068, 01.05.2009.

Research output: Contribution to journalArticle

Lott, ST, Chen, N, Chandler, DS, Yang, Q, Wang, L, Rodriguez, M, Xie, H, Balasenthil, S, Buchholz, TA, Sahin, AA, Chaung, K, Zhang, B, Olufemi, SE, Chen, J, Adams, H, Band, V, El-Naggar, AK, Frazier, ML, Keyomarsi, K, Hunt, KK, Sen, S, Haffty, B, Hewitt, SM, Krahe, R & Killary, AM 2009, 'DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer', PLoS medicine, vol. 6, no. 5, e1000068. https://doi.org/10.1371/journal.pmed.1000068
Lott, Steven T. ; Chen, Nanyue ; Chandler, Dawn S. ; Yang, Qifeng ; Wang, Luo ; Rodriguez, Marivonne ; Xie, Hongyan ; Balasenthil, Seetharaman ; Buchholz, Thomas A. ; Sahin, Aysegul A. ; Chaung, Katrina ; Zhang, Baili ; Olufemi, Shodimu Emmanu ; Chen, Jinyun ; Adams, Henry ; Band, Vimla ; El-Naggar, Adel K. ; Frazier, Marsha L. ; Keyomarsi, Khandan ; Hunt, Kelly K. ; Sen, Subrata ; Haffty, Bruce ; Hewitt, Stephen M. ; Krahe, Ralf ; Killary, Ann McNeill. / DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer. In: PLoS medicine. 2009 ; Vol. 6, No. 5.
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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. Methods and Findings: 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 (ER2, PR2, HER-22) 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.",
author = "Lott, {Steven T.} and Nanyue Chen and Chandler, {Dawn S.} and Qifeng Yang and Luo Wang and Marivonne Rodriguez and Hongyan Xie and Seetharaman Balasenthil and Buchholz, {Thomas A.} and Sahin, {Aysegul A.} and Katrina Chaung and Baili Zhang and Olufemi, {Shodimu Emmanu} and Jinyun Chen and Henry Adams and Vimla Band and El-Naggar, {Adel K.} and Frazier, {Marsha L.} and Khandan Keyomarsi and Hunt, {Kelly K.} and Subrata Sen and Bruce Haffty and Hewitt, {Stephen M.} and Ralf Krahe and Killary, {Ann McNeill}",
year = "2009",
month = "5",
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doi = "10.1371/journal.pmed.1000068",
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TY - JOUR

T1 - DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer

AU - Lott, Steven T.

AU - Chen, Nanyue

AU - Chandler, Dawn S.

AU - Yang, Qifeng

AU - Wang, Luo

AU - Rodriguez, Marivonne

AU - Xie, Hongyan

AU - Balasenthil, Seetharaman

AU - Buchholz, Thomas A.

AU - Sahin, Aysegul A.

AU - Chaung, Katrina

AU - Zhang, Baili

AU - Olufemi, Shodimu Emmanu

AU - Chen, Jinyun

AU - Adams, Henry

AU - Band, Vimla

AU - El-Naggar, Adel K.

AU - Frazier, Marsha L.

AU - Keyomarsi, Khandan

AU - Hunt, Kelly K.

AU - Sen, Subrata

AU - Haffty, Bruce

AU - Hewitt, Stephen M.

AU - Krahe, Ralf

AU - Killary, Ann McNeill

PY - 2009/5/1

Y1 - 2009/5/1

N2 - 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. Methods and Findings: 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 (ER2, PR2, HER-22) 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.

AB - 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. Methods and Findings: 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 (ER2, PR2, HER-22) 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.

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