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In vivo evidence of htid suppressive activity on ErbB-2 in breast cancers over expressing the receptor.

Kurzik-Dumke U, Hörner M, Nicotra MR, Koslowski M, Natali PG - J Transl Med (2010)

Bottom Line: Altered ErbB-2 signalling is associated with an unfavourable prognosis in about 30% of human breast malignancies.A statistically significant inverse correlation between htid and ErbB-2 expression was found in human breast (p < 0,0001) and non-mammary tumors (p < 0,007), and in transgenic mice carrying the rat HER-2/neu oncogene.Our findings provide in vivo evidence that htid is a tissue independent and evolutionarily conserved suppressor of ErbB-2.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Medical Microbiology and Hygiene, Comparative Tumor Biology Group, University Medical Center, Johannes Gutenberg University, Obere Zahlbacher Str 63, 55131 Mainz, Germany. kurzik@uni-mainz.de

ABSTRACT

Background: Htid encoded proteins are physiological partners of a wide spectrum of molecules relevant to neoplastic transformation. One of the molecular ligands of the cytosolic hTid-L and hTid-I forms is the ErbB-2 receptor variably over expressed in diverse solid tumors. Altered ErbB-2 signalling is associated with an unfavourable prognosis in about 30% of human breast malignancies.

Methods: We evaluated htid and HER-2 expression by quantitative real time PCR in tumors of different TNMG status and by immunohistochemistry in a cohort of breast tumors of the Luminal A, B, HER-2 and triple negative subtype.

Results: The RT-PCR analysis revealed that aberrant expression of all three htid forms correlates with malignant transformation. Furthermore, elevated hTid-L expression can be associated with less aggressive tumors. The immunohistochemical testing revealed that tumors of the luminal A subtype are characterized by a high level of htid (81%). In contrast htid expression is significantly lower in tumors of the Luminal B (20%) and HER-2 (18%) subtype over expressing the receptor and in the triple negative (40%) more aggressive malignancies. A statistically significant inverse correlation between htid and ErbB-2 expression was found in human breast (p < 0,0001) and non-mammary tumors (p < 0,007), and in transgenic mice carrying the rat HER-2/neu oncogene.

Conclusions: Our findings provide in vivo evidence that htid is a tissue independent and evolutionarily conserved suppressor of ErbB-2.

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Comparative analysis of htid and HER-2 expression in breast and non breast tumors. The detection of htid was performed as described in the legend to Figure 1. The ErbB-2 oncogene was detected using a monoclonal anti ErbB-2 antibody (AO485). Weak htid expression is detectable in HER-2 over expressing breast tumors of the luminal B (A, B) and HER-2 (C, D) subtype as well as in a renal clear cell carcinoma (E, F). (Original magnification: 250×).
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Figure 2: Comparative analysis of htid and HER-2 expression in breast and non breast tumors. The detection of htid was performed as described in the legend to Figure 1. The ErbB-2 oncogene was detected using a monoclonal anti ErbB-2 antibody (AO485). Weak htid expression is detectable in HER-2 over expressing breast tumors of the luminal B (A, B) and HER-2 (C, D) subtype as well as in a renal clear cell carcinoma (E, F). (Original magnification: 250×).

Mentions: In view of the above findings which are consistent with the in vitro findings of hTid oncosuppressive activity on ErbB-2 [15], we focussed our further investigation on the analysis of the in vivo correlation between htid and HER-2 expression. Regarding the expression of the two target genes the following patterns were compared: double positive (HER-2 +/tid +), double negative (HER-2 -/tid -) and positive/negative (HER-2 +/tid -; tid +/HER-2 -). Specimens characterized by lack or faint expression of the target antigens were defined as negative. Samples showing moderate (+) to strong (2+/3+) signals by staining them with anti hTid antibodies and 3+ or 2+/Fish+ stain using antibodies against ErbB-2 were defined as positive. In that context we assayed comparatively the expression levels of the proteins encoded by the two target genes in 24 primary tumors over expressing the receptor (17 of the HER-2 and 7 of the luminal B subtype) and 34 ErbB-2 negative tumors (16 luminal A, 8 luminal B and 10 of the triple negative subtype) as well as in metastatic lesions over expressing the TRK receptor by staining with anti-Tid [6,7,13] and antibodies against ErbB-2. The results of this analysis are summarized in Table 3A and Figure 2A-D. They clearly demonstrate that the expression of the two targets investigated is inversely correlated in both primary (p < in 0,0001) and in metastatic (p < 0.023) mammary tumors (not shown). Since ErbB-2 over expression may occur also in other epithelial cancers [18], we performed a comparative staining of HER-2 and htid in non mammary carcinomas characterized by elevated levels of ErbB-2 (10 cases) and in cancers displaying low levels of the receptor (8 cases). This study (Table 3B) also yielded a highly significant inverse correlation (p < 0,007) with respect to the expression levels of the two tumor genes investigated (Figure 2E, F).


In vivo evidence of htid suppressive activity on ErbB-2 in breast cancers over expressing the receptor.

Kurzik-Dumke U, Hörner M, Nicotra MR, Koslowski M, Natali PG - J Transl Med (2010)

Comparative analysis of htid and HER-2 expression in breast and non breast tumors. The detection of htid was performed as described in the legend to Figure 1. The ErbB-2 oncogene was detected using a monoclonal anti ErbB-2 antibody (AO485). Weak htid expression is detectable in HER-2 over expressing breast tumors of the luminal B (A, B) and HER-2 (C, D) subtype as well as in a renal clear cell carcinoma (E, F). (Original magnification: 250×).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2909173&req=5

Figure 2: Comparative analysis of htid and HER-2 expression in breast and non breast tumors. The detection of htid was performed as described in the legend to Figure 1. The ErbB-2 oncogene was detected using a monoclonal anti ErbB-2 antibody (AO485). Weak htid expression is detectable in HER-2 over expressing breast tumors of the luminal B (A, B) and HER-2 (C, D) subtype as well as in a renal clear cell carcinoma (E, F). (Original magnification: 250×).
Mentions: In view of the above findings which are consistent with the in vitro findings of hTid oncosuppressive activity on ErbB-2 [15], we focussed our further investigation on the analysis of the in vivo correlation between htid and HER-2 expression. Regarding the expression of the two target genes the following patterns were compared: double positive (HER-2 +/tid +), double negative (HER-2 -/tid -) and positive/negative (HER-2 +/tid -; tid +/HER-2 -). Specimens characterized by lack or faint expression of the target antigens were defined as negative. Samples showing moderate (+) to strong (2+/3+) signals by staining them with anti hTid antibodies and 3+ or 2+/Fish+ stain using antibodies against ErbB-2 were defined as positive. In that context we assayed comparatively the expression levels of the proteins encoded by the two target genes in 24 primary tumors over expressing the receptor (17 of the HER-2 and 7 of the luminal B subtype) and 34 ErbB-2 negative tumors (16 luminal A, 8 luminal B and 10 of the triple negative subtype) as well as in metastatic lesions over expressing the TRK receptor by staining with anti-Tid [6,7,13] and antibodies against ErbB-2. The results of this analysis are summarized in Table 3A and Figure 2A-D. They clearly demonstrate that the expression of the two targets investigated is inversely correlated in both primary (p < in 0,0001) and in metastatic (p < 0.023) mammary tumors (not shown). Since ErbB-2 over expression may occur also in other epithelial cancers [18], we performed a comparative staining of HER-2 and htid in non mammary carcinomas characterized by elevated levels of ErbB-2 (10 cases) and in cancers displaying low levels of the receptor (8 cases). This study (Table 3B) also yielded a highly significant inverse correlation (p < 0,007) with respect to the expression levels of the two tumor genes investigated (Figure 2E, F).

Bottom Line: Altered ErbB-2 signalling is associated with an unfavourable prognosis in about 30% of human breast malignancies.A statistically significant inverse correlation between htid and ErbB-2 expression was found in human breast (p < 0,0001) and non-mammary tumors (p < 0,007), and in transgenic mice carrying the rat HER-2/neu oncogene.Our findings provide in vivo evidence that htid is a tissue independent and evolutionarily conserved suppressor of ErbB-2.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Medical Microbiology and Hygiene, Comparative Tumor Biology Group, University Medical Center, Johannes Gutenberg University, Obere Zahlbacher Str 63, 55131 Mainz, Germany. kurzik@uni-mainz.de

ABSTRACT

Background: Htid encoded proteins are physiological partners of a wide spectrum of molecules relevant to neoplastic transformation. One of the molecular ligands of the cytosolic hTid-L and hTid-I forms is the ErbB-2 receptor variably over expressed in diverse solid tumors. Altered ErbB-2 signalling is associated with an unfavourable prognosis in about 30% of human breast malignancies.

Methods: We evaluated htid and HER-2 expression by quantitative real time PCR in tumors of different TNMG status and by immunohistochemistry in a cohort of breast tumors of the Luminal A, B, HER-2 and triple negative subtype.

Results: The RT-PCR analysis revealed that aberrant expression of all three htid forms correlates with malignant transformation. Furthermore, elevated hTid-L expression can be associated with less aggressive tumors. The immunohistochemical testing revealed that tumors of the luminal A subtype are characterized by a high level of htid (81%). In contrast htid expression is significantly lower in tumors of the Luminal B (20%) and HER-2 (18%) subtype over expressing the receptor and in the triple negative (40%) more aggressive malignancies. A statistically significant inverse correlation between htid and ErbB-2 expression was found in human breast (p < 0,0001) and non-mammary tumors (p < 0,007), and in transgenic mice carrying the rat HER-2/neu oncogene.

Conclusions: Our findings provide in vivo evidence that htid is a tissue independent and evolutionarily conserved suppressor of ErbB-2.

Show MeSH
Related in: MedlinePlus