Per my commentary over on Trickle about the Eos/PCOP tie-up, the description of the targets was very general.
Message 16245729
I started plugging the names of the collaborators into MedLine, hoping to find more specific clues. Most of what they're doing these days seems to focus on breast and colon cancer. My understanding of all of this is slight, but parking the relevant abstracts, anyhow, in the hope a qualified biofreak might find something useful. That is if we can get one at all interested in looking.
Mind that this isn't neccesarily tied to Eos. I can't find diddly from anyone who works directly for them, but I haven't tried the SAB yet.
>>Overexpression of the steroid receptor coactivator AIB1 in breast cancer correlates with the absence of estrogen and progesterone receptors and positivity for p53 and HER2/neu.
Cancer Res 2001 Feb 1;61(3):903-7 (ISSN: 0008-5472)
Bouras T; Southey MC; Venter DJ
Department to Pathology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
The gene for the steroid receptor coactivator amplified in breast cancer 1 (AIBI), located on chromosome 20q12, is overexpressed at the mRNA level in up to 60% of primary breast carcinomas; however, only 5% of these tumors show DNA amplification. The transcription factors and signaling pathways relevant to breast cancer, which in the absence of DNA amplification are responsible for and targeted by elevated levels of AIBI mRNA, are unknown. In the present study, in situ hybridization was used to examine AIB1 mRNA expression in 93 breast carcinomas of varying histological grade and immunohistochemical profile. AIB1 mRNA was overexpressed relative to normal breast tissue in 26 of 83 (31%) invasive tumors. This was found to associate with high tumor grade (P = 0.0006), lack of immunohistochemical staining for the steroid receptors estrogen receptor (P = 0.002) and progesterone receptor (P = 0.002), and strong protein staining for p53 (P = 0.01) and HER2/neu (P = 0.002). These findings suggest that AIB1 overexpression may impact on breast cancer by a mechanism not wholly dependent on steroid receptor coexpression and which may involve other oncogenic events, such as p53 protein stabilization and HER2/neu overexpression.<<
>>The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer [In Process Citation]
Proc Natl Acad Sci U S A 2001 Dec 4;98(25):14452-7 (ISSN: 0027-8424)
Visvader JE; Venter D; Hahm K; Santamaria M; Sum EY; O'Reilly L; White D; Williams R; Armes J; Lindeman GJ The Walter and Eliza Hall Institute of Medical Research and Bone Marrow Research Laboratories, Melbourne, Victoria 3050, Australia. visvader@wehi.edu.au <mailto:visvader@wehi.edu.au>.
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.<<
>>MMTV promoter hypomethylation is linked to spontaneous and MNU associated c-neu expression and mammary carcinogenesis in MMTV c-neu transgenic mice.
Oncogene 2001 Sep 20;20(42):6009-17 (ISSN: 0950-9232)
Zhou H; Chen WD; Qin X; Lee K; Liu L; Markowitz SD; Gerson SL
Division of Hematology/Oncology and Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106-4937, USA.
The erbB family of receptor tyrosine kinases is frequently implicated in neoplasia. Amplification and overexpression of erbB2/neu has been found in 20 to 40% of human breast cancers. Previous studies using MMTV/c-neu transgenic mice have linked rat neu overexpression to mammary tumor development. In this study, we provide evidence that rat neu overexpression in mammary tumors of MMTV/c-neu transgenic mice is always associated with demethylation of the MMTV promoter, whereas the normal mammary glands of these transgenic mice always contain specific methylated regions of the MMTV promoter. In addition, after exposure to N-methyl-N-nitrosourea (MNU), the latency of mammary tumor development is significantly reduced and again is also associated with MMTV promoter demethylation. Thus, the transition from methylation to hypomethylation of the MMTV promoter induces high-level expression of c-neu and appears to be a prerequisite for transformation from normal to malignant mammary epithelium, either spontaneously or after carcinogen exposure. Expression of transgenic c-neu from the demethylated MMTV promoter appears to be an early event that allows outgrowth of mammary epithelium predisposed to malignant transformation.<<
>>Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.
Proc Natl Acad Sci U S A 1998 Jul 21;95(15):8698-702 (ISSN: 0027-8424)
Veigl ML; Kasturi L; Olechnowicz J; Ma AH; Lutterbaugh JD; Periyasamy S; Li GM; Drummond J; Modrich PL; Sedwick WD; Markowitz SD
Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA.
Mutations of DNA mismatch repair genes, including the hMLH1 gene, have been linked to human colon and other cancers in which defective DNA repair is evidenced by the associated instability of DNA microsatellite sequences (MSI). Germ-line hMLH1 mutations are causally associated with inherited MSI colon cancer, and somatic mutations are causally associated with sporadic MSI colon cancer. Previously however, we demonstrated that in many sporadic MSI colon cancers hMLH1 and all other DNA mismatch repair genes are wild type. To investigate this class of tumors further, we examined a group of MSI cancer cell lines, most of which were documented as established from antecedent MSI-positive malignant tumors. In five of six such cases we found that hMLH1 protein was absent, even though hMLH1-coding sequences were wild type. In each such case, absence of hMLH1 protein was associated with the methylation of the hMLH1 gene promoter. Furthermore, in each case, treatment with the demethylating agent 5-azacytidine induced expression of the absent hMLH1 protein. Moreover, in single cell clones, hMLH1 expression could be turned on, off, and on again by 5-azacytidine exposure, washout, and reexposure. This epigenetic inactivation of hMLH1 additionally accounted for the silencing of both maternal and paternal tumor hMLH1 alleles, both of which could be reactivated by 5-azacytidine. In summary, substantial numbers of human MSI cancers appear to arise by hMLH1 silencing via an epigenetic mechanism that can inactivate both of the hMLH1 alleles. Promoter methylation is intimately associated with this epigenetic silencing mechanism.<<
>>A potential role for activated HER-2 in prostate cancer.
Semin Oncol 2000 Dec;27(6 Suppl 11):76-83; discussion 92-100 (ISSN: 0093-7754)
Agus DB; Akita RW; Fox WD; Lofgren JA; Higgins B; Maiese K; Scher HI; Sliwkowski MX
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
The epidermal growth factor (also known as HER or ErbB) family of receptor tyrosine kinases are important mediators of cell growth, differentiation, and survival. At present there are 10 ligands that bind directly to epidermal growth factor, HER-3, or HER-4. Although none of these ligands bind directly to HER-2, it is recruited to these receptor complexes and also becomes activated. A monoclonal antibody directed against HER-2, 2C4, inhibits the association of HER-2 with other HER family members. Ligand-activated HER-2 may also play a role in cancers, particularly those that do not overexpress HER-2 at high levels. For example, when prostate cancers progress from an androgen-dependent to an androgen-independent phenotype, epidermal growth factor pathways are frequently activated. 2C4 will inhibit the growth of both androgen-dependent and androgen-independent prostate tumors grown as xenografts in athymic mice.<<
Cheers, Tuck
I started to plugging the names of the collaborators into MedLine, hoping to find more specific clues. Most of what they're doing these days seems to focus on breast and colon cancer. My understanding of all of this is slight, but parking the relevant abstracts, anyhow, in the hope a qualified biofreak might find something useful. That is if we can get one at all interested in looking.
Mind that this isn't neccesarily tied to Eos. I can't find diddly from anyone who works directly for them, but I haven't tried the SAB yet.
>>Overexpression of the steroid receptor coactivator AIB1 in breast cancer correlates with the absence of estrogen and progesterone receptors and positivity for p53 and HER2/neu.
Cancer Res 2001 Feb 1;61(3):903-7 (ISSN: 0008-5472)
Bouras T; Southey MC; Venter DJ
Department to Pathology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
The gene for the steroid receptor coactivator amplified in breast cancer 1 (AIBI), located on chromosome 20q12, is overexpressed at the mRNA level in up to 60% of primary breast carcinomas; however, only 5% of these tumors show DNA amplification. The transcription factors and signaling pathways relevant to breast cancer, which in the absence of DNA amplification are responsible for and targeted by elevated levels of AIBI mRNA, are unknown. In the present study, in situ hybridization was used to examine AIB1 mRNA expression in 93 breast carcinomas of varying histological grade and immunohistochemical profile. AIB1 mRNA was overexpressed relative to normal breast tissue in 26 of 83 (31%) invasive tumors. This was found to associate with high tumor grade (P = 0.0006), lack of immunohistochemical staining for the steroid receptors estrogen receptor (P = 0.002) and progesterone receptor (P = 0.002), and strong protein staining for p53 (P = 0.01) and HER2/neu (P = 0.002). These findings suggest that AIB1 overexpression may impact on breast cancer by a mechanism not wholly dependent on steroid receptor coexpression and which may involve other oncogenic events, such as p53 protein stabilization and HER2/neu overexpression.<<
>>The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer [In Process Citation]
Proc Natl Acad Sci U S A 2001 Dec 4;98(25):14452-7 (ISSN: 0027-8424)
Visvader JE; Venter D; Hahm K; Santamaria M; Sum EY; O'Reilly L; White D; Williams R; Armes J; Lindeman GJ The Walter and Eliza Hall Institute of Medical Research and Bone Marrow Research Laboratories, Melbourne, Victoria 3050, Australia. visvader@wehi.edu.au <mailto:visvader@wehi.edu.au>.
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.<<
>>MMTV promoter hypomethylation is linked to spontaneous and MNU associated c-neu expression and mammary carcinogenesis in MMTV c-neu transgenic mice.
Oncogene 2001 Sep 20;20(42):6009-17 (ISSN: 0950-9232)
Zhou H; Chen WD; Qin X; Lee K; Liu L; Markowitz SD; Gerson SL
Division of Hematology/Oncology and Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106-4937, USA.
The erbB family of receptor tyrosine kinases is frequently implicated in neoplasia. Amplification and overexpression of erbB2/neu has been found in 20 to 40% of human breast cancers. Previous studies using MMTV/c-neu transgenic mice have linked rat neu overexpression to mammary tumor development. In this study, we provide evidence that rat neu overexpression in mammary tumors of MMTV/c-neu transgenic mice is always associated with demethylation of the MMTV promoter, whereas the normal mammary glands of these transgenic mice always contain specific methylated regions of the MMTV promoter. In addition, after exposure to N-methyl-N-nitrosourea (MNU), the latency of mammary tumor development is significantly reduced and again is also associated with MMTV promoter demethylation. Thus, the transition from methylation to hypomethylation of the MMTV promoter induces high-level expression of c-neu and appears to be a prerequisite for transformation from normal to malignant mammary epithelium, either spontaneously or after carcinogen exposure. Expression of transgenic c-neu from the demethylated MMTV promoter appears to be an early event that allows outgrowth of mammary epithelium predisposed to malignant transformation.<<
>>Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers.
Proc Natl Acad Sci U S A 1998 Jul 21;95(15):8698-702 (ISSN: 0027-8424)
Veigl ML; Kasturi L; Olechnowicz J; Ma AH; Lutterbaugh JD; Periyasamy S; Li GM; Drummond J; Modrich PL; Sedwick WD; Markowitz SD
Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA.
Mutations of DNA mismatch repair genes, including the hMLH1 gene, have been linked to human colon and other cancers in which defective DNA repair is evidenced by the associated instability of DNA microsatellite sequences (MSI). Germ-line hMLH1 mutations are causally associated with inherited MSI colon cancer, and somatic mutations are causally associated with sporadic MSI colon cancer. Previously however, we demonstrated that in many sporadic MSI colon cancers hMLH1 and all other DNA mismatch repair genes are wild type. To investigate this class of tumors further, we examined a group of MSI cancer cell lines, most of which were documented as established from antecedent MSI-positive malignant tumors. In five of six such cases we found that hMLH1 protein was absent, even though hMLH1-coding sequences were wild type. In each such case, absence of hMLH1 protein was associated with the methylation of the hMLH1 gene promoter. Furthermore, in each case, treatment with the demethylating agent 5-azacytidine induced expression of the absent hMLH1 protein. Moreover, in single cell clones, hMLH1 expression could be turned on, off, and on again by 5-azacytidine exposure, washout, and reexposure. This epigenetic inactivation of hMLH1 additionally accounted for the silencing of both maternal and paternal tumor hMLH1 alleles, both of which could be reactivated by 5-azacytidine. In summary, substantial numbers of human MSI cancers appear to arise by hMLH1 silencing via an epigenetic mechanism that can inactivate both of the hMLH1 alleles. Promoter methylation is intimately associated with this epigenetic silencing mechanism.<<
>>A potential role for activated HER-2 in prostate cancer.
Semin Oncol 2000 Dec;27(6 Suppl 11):76-83; discussion 92-100 (ISSN: 0093-7754)
Agus DB; Akita RW; Fox WD; Lofgren JA; Higgins B; Maiese K; Scher HI; Sliwkowski MX
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
The epidermal growth factor (also known as HER or ErbB) family of receptor tyrosine kinases are important mediators of cell growth, differentiation, and survival. At present there are 10 ligands that bind directly to epidermal growth factor, HER-3, or HER-4. Although none of these ligands bind directly to HER-2, it is recruited to these receptor complexes and also becomes activated. A monoclonal antibody directed against HER-2, 2C4, inhibits the association of HER-2 with other HER family members. Ligand-activated HER-2 may also play a role in cancers, particularly those that do not overexpress HER-2 at high levels. For example, when prostate cancers progress from an androgen-dependent to an androgen-independent phenotype, epidermal growth factor pathways are frequently activated. 2C4 will inhibit the growth of both androgen-dependent and androgen-independent prostate tumors grown as xenografts in athymic mice.<<
Cheers, Tuck |
