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

Abstract

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.

The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity

“…Although the role in the pathology of carcinomas of epithelial origin is not clear, Visvader et al (2001) recently indicated that LMO4 and LDB1 are required to maintain the undifferentiation state of invasive breast carcinoma cells, and the forced expression of LMO4 inhibits differentiation of mammary epithelial cells. Increased expression of LMO4 and LDB1 in less-differentiated oral carcinomas represented in this study suggests an involvement in cellular dedifferentiation.…”

“…The most recently identified member, LMO4, shares only 50% homology with the LIM domains of other LMO proteins. The LMO4 gene is widely distributed in embryonic tissues (Kenny et al, 1998;Sugihara et al, 1998), and involved in negative regulation of breast carcinoma cell differentiation (Visvader et al, 2001). LMO4 binds with a high affinity to the LIM domain-binding proteins, LDB1 (CLIM2, NLI1) and LDB2 (CLIM1) (Agulnick et al, 1996;Jurata et al, 1996;Sugihara et al, 1998).…”

The LIM-only factor LMO4 regulates expression of the BMP7 gene through an HDAC2-dependent mechanism, and controls cell proliferation and apoptosis of mammary epithelial cells

“…These results are specific because the Clim2 antibody was not able to precipitate IgG-precipitated BMP7 promoter (Figure 4c, lane 5). We next tested whether endogenous LMO4 and Clim2 can simultaneously bind to the BMP7 promoter in T47D breast cancer cells, which express relatively high levels of LMO4 (Visvader et al, 2001). In these experiments, where we first precipitated with an LMO4 antibody and then with a Clim2 antibody, both LMO4 and Clim2 associate with the BMP7 promoter (Figure 4d, lane 3).…”

“…The LMO4 gene is most highly expressed in mammary epithelial cells during midpregnancy (Wang et al, 2004), a stage of active proliferation and invasion; interference with the protein (Wang et al, 2004) or deletion of the gene (Sum et al, 2005c) leads to impaired lobuloalveolar development of the mammary gland. LMO4 is overexpressed in over half of primary breast cancers and its expression is associated with a worse prognosis (Visvader et al, 2001;Sum et al, 2005b). In addition, overexpression of LMO4 in the mammary gland of mice leads to hyperplasia and intraepithelial neoplasia (Sum et al, 2005b).…”

ZNF185, an actin–cytoskeleton-associated growth inhibitory LIM protein in prostate cancer

“…In addition, some LIM domain-containing proteins are also involved in pathological processes such as oncogenesis (e.g. EPLIN, Testin and LMO4) (Maul and Chang, 1999;Tatarelli et al, 2000;Tobias et al, 2001;Visvader et al, 2001;Song et al, 2002;Sum et al, 2002;Garvalov et al, 2003). As the full-length ZNF185 cDNA has not been experimentally cloned, the biological function of this LIM domain-containing protein and the pathological relevance in PCa is unknown.…”