The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer

LMO4 belongs to a family of LIM-only transcriptional regulators, the first two members of which are oncoproteins in acute T cell leukemia. We have explored a role for LMO4, initially described as a human breast tumor autoantigen, in developing mammary epithelium and breast oncogenesis. Lmo4 was expressed predominantly in the lobuloalveoli of the mammary gland during pregnancy. Consistent with a role in proliferation, forced expression of this gene inhibited differentiation of mammary epithelial cells. Overexpression of LMO4 mRNA was observed in 5 of 10 human breast cancer cell lines. Moreover, in situ hybridization analysis of 177 primary invasive breast carcinomas revealed overexpression of LMO4 in 56% of specimens. Immunohistochemistry confirmed overexpression in a high percentage (62%) of tumors. These studies imply a role for LMO4 in maintaining proliferation of mammary epithelium and suggest that deregulation of this gene may contribute to breast tumorigenesis.

[1]  S. Culine,et al.  Relating genotype and phenotype in breast cancer: an analysis of the prognostic significance of amplification at eight different genes or loci and of p53 mutations. , 2000, Cancer research.

[2]  N. Carter,et al.  Characterization of the Lmo4 gene encoding a LIM-only protein: genomic organization and comparative chromosomal mapping , 1999, Mammalian Genome.

[3]  G. Giles,et al.  Distinct molecular pathogeneses of early-onset breast cancers in BRCA1 and BRCA2 mutation carriers: a population-based study. , 1999, Cancer research.

[4]  J. Sparano,et al.  Molecular cloning of LMO41, a new human LIM domain gene. , 1999, Biochimica et biophysica acta.

[5]  D. Germain,et al.  Cyclin D1 and D3 associate with the SCF complex and are coordinately elevated in breast cancer , 1999, Oncogene.

[6]  W. Alexander,et al.  Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL‐6 signal transduction , 1999, The EMBO journal.

[7]  M. Rosenfeld,et al.  Mouse deformed epidermal autoregulatory factor 1 recruits a LIM domain factor, LMO-4, and CLIM coregulators. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  T. Rabbitts,et al.  Identification of the LMO4 gene encoding an interaction partner of the LIM-binding protein LDB1/NLI1: a candidate for displacement by LMO proteins in T cell acute leukaemia , 1998, Oncogene.

[9]  W. Kuo,et al.  High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays , 1998, Nature Genetics.

[10]  Y. Saga,et al.  Identification and characterization of LMO4, an LMO gene with a novel pattern of expression during embryogenesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[11]  T. Rabbitts,et al.  LMO T-cell translocation oncogenes typify genes activated by chromosomal translocations that alter transcription and developmental processes. , 1998, Genes & development.

[12]  S. Knuutila,et al.  DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. , 1998, The American journal of pathology.

[13]  J. J. Breen,et al.  LIM domains: multiple roles as adapters and functional modifiers in protein interactions. , 1998, Trends in genetics : TIG.

[14]  Y. Nakamura,et al.  Allelic loss on chromosome 1p is Associated with progression and lymph node metastasis of primary breast carcinoma , 1998, Cancer.

[15]  C. Begley,et al.  Oncostatin M induces the differentiation of breast cancer cells , 1998, International journal of cancer.

[16]  S. Orkin,et al.  The LIM-domain binding protein Ldb1 and its partner LMO2 act as negative regulators of erythroid differentiation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  O. Kallioniemi,et al.  Increased copy number at 17q22‐q24 by CGH in breast cancer is due to high‐level amplification of two separate regions , 1997, Genes, chromosomes & cancer.

[18]  M. Rosenfeld,et al.  A family of LIM domain-associated cofactors confer transcriptional synergism between LIM and Otx homeodomain proteins. , 1997, Genes & development.

[19]  A. Strasser,et al.  Bcl-2, Bcl-xL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death , 1997, Oncogene.

[20]  J. J. Breen,et al.  Interactions of the LIM-domain-binding factor Ldbl with LIM homeodomain proteins , 1996, Nature.

[21]  L. Jurata,et al.  Nuclear LIM interactor, a rhombotin and LIM homeodomain interacting protein, is expressed early in neuronal development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[22]  S. Fineberg,et al.  Cloning of a novel nucleolar guanosine 5'-triphosphate binding protein autoantigen from a breast tumor. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[23]  J. Weissenbach,et al.  Allelic imbalance on chromosome I in human breast cancer. II. Microsatellite repeat analysis , 1995, Genes, chromosomes & cancer.

[24]  T. Rabbitts,et al.  The LIM domain: a new structural motif found in zinc-finger-like proteins. , 1994, Trends in genetics : TIG.

[25]  M. Evans,et al.  The Oncogenic Cysteine-rich LIM domain protein Rbtn2 is essential for erythroid development , 1994, Cell.

[26]  G. Keller,et al.  Novel insights into erythroid development revealed through in vitro differentiation of GATA-1 embryonic stem cells. , 1994, Genes & development.

[27]  J Piper,et al.  Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[28]  T. Rabbitts,et al.  T-cell acute lymphoblastic lymphoma induced in transgenic mice by the RBTN1 and RBTN2 LIM-domain genes. , 1992, Oncogene.

[29]  G. Sclar,et al.  Thymic overexpression of Ttg-1 in transgenic mice results in T-cell acute lymphoblastic leukemia/lymphoma , 1992, Molecular and cellular biology.

[30]  W. Ludwig,et al.  TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). , 1991, Oncogene.

[31]  M. Perutz,et al.  The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Visvader,et al.  Differential expression of the LYL, SCL and E2A helix-loop-helix genes within the hemopoietic system. , 1991, Oncogene.

[33]  T. Rabbitts,et al.  The mechanism of chromosomal translocation t(11;14) involving the T‐cell receptor C delta locus on human chromosome 14q11 and a transcribed region of chromosome 11p15. , 1988, The EMBO journal.