LMO2 promotes tumor cell invasion and metastasis in basal-type breast cancer by altering actin cytoskeleton remodeling

LMO2 is traditionally recognized as a pivotal transcriptional regulator during embryonic hematopoiesis and angionenesis, and its ectopic expression in T lymphocyte progenitors is closely correlated to the onset of acute T lymphocytic leukemia. However, recently studies revealed complicated expression features and dual functions of LMO2 on tumor behaviors in a variety of cancer types, including breast cancers. Basal-type breast cancer is one of the breast cancer subtypes and a prognostically unfavorable subtype among all breast cancers. Herein we found that in basal-type breast cancer specifically, high LMO2 expression was positively correlated with lymph node metastases in patients, promoted tumor cell migration and invasion and increased distant metastasis in SCID mice. Moreover, the novel function of LMO2 was achieved by its predominantly cytoplasmic location and interaction with cofilin1, which is a critical regulator in actin cytoskeleton dynamics. These findings suggest a subtype-dependent role of LMO2 in breast cancers and the potential of LMO2 as a subtype-specific biomarker for clinical practice.

[1]  Chao Wu,et al.  LMO2 attenuates tumor growth by targeting the Wnt signaling pathway in breast and colorectal cancer , 2016, Scientific Reports.

[2]  Chao Wu,et al.  LMO2 blocks the UBA6-USE1 interaction and downstream FAT10ylation by targeting the ubiquitin fold domain of UBA6. , 2016, Biochemical and biophysical research communications.

[3]  F. Tang,et al.  Tracing haematopoietic stem cell formation at single-cell resolution , 2016, Nature.

[4]  I. Nakano,et al.  The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells , 2015, Cell Death and Differentiation.

[5]  S. Pileri,et al.  Detection of LIM domain only 2 (LMO2) in normal human tissues and haematopoietic and non‐haematopoietic tumours using a newly developed rabbit monoclonal antibody , 2012, Histopathology.

[6]  John Condeelis,et al.  Directed cell invasion and migration during metastasis. , 2012, Current opinion in cell biology.

[7]  I. Lossos,et al.  LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome , 2011, Haematologica.

[8]  S. Alahari,et al.  Role of Rho GTPases and their regulators in cancer progression. , 2011, Frontiers in bioscience.

[9]  Shuang Yang,et al.  Identification of DeltaEF1 as a novel target that is negatively regulated by LMO2 in T‐cell leukemia , 2010, European journal of haematology.

[10]  Gerhard Christofori,et al.  Mechanisms of Motility in Metastasizing Cells , 2010, Molecular Cancer Research.

[11]  C. D. de Graaf,et al.  The Lmo2 Oncogene Initiates Leukemia in Mice by Inducing Thymocyte Self-Renewal , 2010, Science.

[12]  K. Ohuchida,et al.  LMO2 is a novel predictive marker for a better prognosis in pancreatic cancer. , 2009, Neoplasia.

[13]  Debra L Winkeljohn.  Triple-negative breast cancer. , 2008, Clinical journal of oncology nursing.

[14]  T. Zhu,et al.  Downregulation of microRNA-142 by proto-oncogene LMO2 and its co-factors , 2008, Leukemia.

[15]  Robert Tibshirani,et al.  LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  John Condeelis,et al.  The cofilin pathway in breast cancer invasion and metastasis , 2007, Nature Reviews Cancer.

[17]  X. Wang,et al.  A novel transcript of the LMO2 gene, LMO2-c, is regulated by GATA-1 and PU.1 and encodes an antagonist of LMO2 , 2007, Leukemia.

[18]  I. Lossos,et al.  The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas. , 2007, Blood.

[19]  R. Scott,et al.  LIM kinases: function, regulation and association with human disease , 2007, Journal of Molecular Medicine.

[20]  X. Guan,et al.  The significance of LMO2 expression in the progression of prostate cancer , 2007, The Journal of pathology.

[21]  V. Deleuze,et al.  TAL-1/SCL and Its Partners E47 and LMO2 Up-Regulate VE-Cadherin Expression in Endothelial Cells , 2007, Molecular and Cellular Biology.

[22]  D. Yamazaki,et al.  Regulation of cancer cell motility through actin reorganization , 2005, Cancer science.

[23]  Ash A. Alizadeh,et al.  Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. , 2004, The New England journal of medicine.

[24]  T. Rabbitts,et al.  The oncogenic T cell LIM‐protein Lmo2 forms part of a DNA‐binding complex specifically in immature T cells , 1998, The EMBO journal.

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

[26]  T. Rabbitts,et al.  The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  T. Rabbitts,et al.  The LIM‐only protein Lmo2 is a bridging molecule assembling an erythroid, DNA‐binding complex which includes the TAL1, E47, GATA‐1 and Ldb1/NLI proteins , 1997, The EMBO journal.

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

[29]  T. Langford,et al.  T cell tumours of disparate phenotype in mice transgenic for Rbtn-2. , 1994, Oncogene.

[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]  T. Rabbitts,et al.  The role of LMO2 in development and in T cell leukemia after chromosomal translocation or retroviral insertion. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.