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Expression of HER-2 affects patient survival and paclitaxel sensitivity in endometrial cancer.

Mori N, Kyo S, Nakamura M, Hashimoto M, Maida Y, Mizumoto Y, Takakura M, Ohno S, Kiyono T, Inoue M - Br. J. Cancer (2010)

Bottom Line: Kaplan-Meier analysis revealed that high HER-2 expression was a factor that negatively influenced the progression-free and overall survival rate (P<0.05), and multivariate analysis showed high HER-2 expression to be an independent prognostic factor.Subsequently, we performed in vitro knockdown analysis to investigate the linkage between HER-2 expression and PI3K-AKT pathways.As the PI3K-AKT pathway is known to have crucial roles in anticancer drug sensitivity, we examined the involvement of HER-2 in sensitivity to paclitaxel.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.

ABSTRACT

Background: Disabled phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase/extracellular signal-regulated kinase signalling is involved in endometrial carcinogenesis, and there is evidence that expression of epidermal growth factor receptor (EGFR) family members has a role in such intracellular signalling pathways. This study analysed the prognostic impact of EGFR family expression in endometrial cancer in relation to PI3K-AKT and MAPK-ERK signalling, as well as drug sensitivity.

Methods and results: Immunohistochemical analysis using 63 surgical specimens of endometrioid-type endometrial cancers revealed that EGFR, human epidermal growth factor receptor (HER)-2 and HER-4 were expressed in 25 (39.7%) of 63, 26 (41.3%) of 63 and 31 (49.2%) of 63 tumours, respectively. Gene amplification of HER-2 was observed in 2 of 26 patients with high HER-2 expression. Kaplan-Meier analysis revealed that high HER-2 expression was a factor that negatively influenced the progression-free and overall survival rate (P<0.05), and multivariate analysis showed high HER-2 expression to be an independent prognostic factor. Subsequently, we performed in vitro knockdown analysis to investigate the linkage between HER-2 expression and PI3K-AKT pathways. Short interfering RNA (siRNA)-based knockdown of HER-2 in endometrial cancer cells led to a significant reduction in phosphorylated AKT (p-AKT) expression, indicating the existence of a HER-2/PI3K-AKT axis. As the PI3K-AKT pathway is known to have crucial roles in anticancer drug sensitivity, we examined the involvement of HER-2 in sensitivity to paclitaxel. Short interfering RNA-based knockdown of HER-2 conferred increased sensitivity to paclitaxel in endometrial cancer cells, attenuating the induction of p-AKT on paclitaxel stimulation, which was cancelled by inactivating AKT by the introduction of a dominant-negative form.

Conclusion: HER-2 is a significant prognostic factor of endometrioid-type endometrial cancer, as well as a key molecule that affects paclitaxel sensitivity by HER-2 interaction with the PI3K-AKT pathway.

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Immunohistochemistry of HER-2 in endometrioid-type endometrial cancer. Representative results of each score are shown (A: score 0; B: score 1; C: score 2 ( × 200) and D: score 3 ( × 400)). The definition of each score is described in Materials and Methods. A breast cancer specimen (E) with HER-2 expression was used as the positive control for appropriate staining conditions ( × 400). (F) CISH analysis of the case (D) showing high levels of HER-2 amplification ( × 400). Brown dots show the large gene copy clusters.
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fig1: Immunohistochemistry of HER-2 in endometrioid-type endometrial cancer. Representative results of each score are shown (A: score 0; B: score 1; C: score 2 ( × 200) and D: score 3 ( × 400)). The definition of each score is described in Materials and Methods. A breast cancer specimen (E) with HER-2 expression was used as the positive control for appropriate staining conditions ( × 400). (F) CISH analysis of the case (D) showing high levels of HER-2 amplification ( × 400). Brown dots show the large gene copy clusters.

Mentions: We first investigated the expression of EGFR family members EGFR, HER-2 and HER-4 by immunohistochemistry using 63 surgical specimens of endometrioid-type endometrial cancers, on the basis of the known finding that HER-3 expression is not upregulated in endometrial cancer (Ejskjaer et al, 2007). The expression of HER-2 was classified into two levels, namely, low (score 0 or 1) and high (score 2 or 3), whereas that of EGFR/HER-4 was also classified into two levels, namely, low (− or +) and high (++ or +++). High expressions of EGFR, HER-2 and HER-4 were observed in 25 (39.7%) of 63, 26 (41.3%) of 63 and 31 (49.2%) of 63 tumours, in which 48.0% (12 out of 25), 61.5% (16 out of 26) and 54.8% (17 out of 31), respectively, exhibited heterogeneous expression within tumours. There was no preferential expression of these members in any of the specific tumour regions, such as in the invasive front or at the centre of tumours or in areas of squamous differentiation. Representative staining patterns of HER-2 are shown in Figure 1. Human epidermal growth factor receptor-2 gene amplification was further analysed in 26 patients with a high HER-2 expression by CISH, and two patients (FIGO1b, G1 and FIGO3c, G2, respectively) with score 3 HER-2 expression were found to have HER-2 gene amplification. We next examined the relationship between these expression patterns and the clinicopathological characteristics of the specimens (Table 1). However, no statistically significant correlation was observed between them.


Expression of HER-2 affects patient survival and paclitaxel sensitivity in endometrial cancer.

Mori N, Kyo S, Nakamura M, Hashimoto M, Maida Y, Mizumoto Y, Takakura M, Ohno S, Kiyono T, Inoue M - Br. J. Cancer (2010)

Immunohistochemistry of HER-2 in endometrioid-type endometrial cancer. Representative results of each score are shown (A: score 0; B: score 1; C: score 2 ( × 200) and D: score 3 ( × 400)). The definition of each score is described in Materials and Methods. A breast cancer specimen (E) with HER-2 expression was used as the positive control for appropriate staining conditions ( × 400). (F) CISH analysis of the case (D) showing high levels of HER-2 amplification ( × 400). Brown dots show the large gene copy clusters.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2966616&req=5

fig1: Immunohistochemistry of HER-2 in endometrioid-type endometrial cancer. Representative results of each score are shown (A: score 0; B: score 1; C: score 2 ( × 200) and D: score 3 ( × 400)). The definition of each score is described in Materials and Methods. A breast cancer specimen (E) with HER-2 expression was used as the positive control for appropriate staining conditions ( × 400). (F) CISH analysis of the case (D) showing high levels of HER-2 amplification ( × 400). Brown dots show the large gene copy clusters.
Mentions: We first investigated the expression of EGFR family members EGFR, HER-2 and HER-4 by immunohistochemistry using 63 surgical specimens of endometrioid-type endometrial cancers, on the basis of the known finding that HER-3 expression is not upregulated in endometrial cancer (Ejskjaer et al, 2007). The expression of HER-2 was classified into two levels, namely, low (score 0 or 1) and high (score 2 or 3), whereas that of EGFR/HER-4 was also classified into two levels, namely, low (− or +) and high (++ or +++). High expressions of EGFR, HER-2 and HER-4 were observed in 25 (39.7%) of 63, 26 (41.3%) of 63 and 31 (49.2%) of 63 tumours, in which 48.0% (12 out of 25), 61.5% (16 out of 26) and 54.8% (17 out of 31), respectively, exhibited heterogeneous expression within tumours. There was no preferential expression of these members in any of the specific tumour regions, such as in the invasive front or at the centre of tumours or in areas of squamous differentiation. Representative staining patterns of HER-2 are shown in Figure 1. Human epidermal growth factor receptor-2 gene amplification was further analysed in 26 patients with a high HER-2 expression by CISH, and two patients (FIGO1b, G1 and FIGO3c, G2, respectively) with score 3 HER-2 expression were found to have HER-2 gene amplification. We next examined the relationship between these expression patterns and the clinicopathological characteristics of the specimens (Table 1). However, no statistically significant correlation was observed between them.

Bottom Line: Kaplan-Meier analysis revealed that high HER-2 expression was a factor that negatively influenced the progression-free and overall survival rate (P<0.05), and multivariate analysis showed high HER-2 expression to be an independent prognostic factor.Subsequently, we performed in vitro knockdown analysis to investigate the linkage between HER-2 expression and PI3K-AKT pathways.As the PI3K-AKT pathway is known to have crucial roles in anticancer drug sensitivity, we examined the involvement of HER-2 in sensitivity to paclitaxel.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.

ABSTRACT

Background: Disabled phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase/extracellular signal-regulated kinase signalling is involved in endometrial carcinogenesis, and there is evidence that expression of epidermal growth factor receptor (EGFR) family members has a role in such intracellular signalling pathways. This study analysed the prognostic impact of EGFR family expression in endometrial cancer in relation to PI3K-AKT and MAPK-ERK signalling, as well as drug sensitivity.

Methods and results: Immunohistochemical analysis using 63 surgical specimens of endometrioid-type endometrial cancers revealed that EGFR, human epidermal growth factor receptor (HER)-2 and HER-4 were expressed in 25 (39.7%) of 63, 26 (41.3%) of 63 and 31 (49.2%) of 63 tumours, respectively. Gene amplification of HER-2 was observed in 2 of 26 patients with high HER-2 expression. Kaplan-Meier analysis revealed that high HER-2 expression was a factor that negatively influenced the progression-free and overall survival rate (P<0.05), and multivariate analysis showed high HER-2 expression to be an independent prognostic factor. Subsequently, we performed in vitro knockdown analysis to investigate the linkage between HER-2 expression and PI3K-AKT pathways. Short interfering RNA (siRNA)-based knockdown of HER-2 in endometrial cancer cells led to a significant reduction in phosphorylated AKT (p-AKT) expression, indicating the existence of a HER-2/PI3K-AKT axis. As the PI3K-AKT pathway is known to have crucial roles in anticancer drug sensitivity, we examined the involvement of HER-2 in sensitivity to paclitaxel. Short interfering RNA-based knockdown of HER-2 conferred increased sensitivity to paclitaxel in endometrial cancer cells, attenuating the induction of p-AKT on paclitaxel stimulation, which was cancelled by inactivating AKT by the introduction of a dominant-negative form.

Conclusion: HER-2 is a significant prognostic factor of endometrioid-type endometrial cancer, as well as a key molecule that affects paclitaxel sensitivity by HER-2 interaction with the PI3K-AKT pathway.

Show MeSH
Related in: MedlinePlus