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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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Kaplan–Meier survival curves of 63 patients with endometrial cancer in relation to HER-2 expression. (A) Relapse-free survival (B) Overall survival.
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fig2: Kaplan–Meier survival curves of 63 patients with endometrial cancer in relation to HER-2 expression. (A) Relapse-free survival (B) Overall survival.

Mentions: Next, the survival impact of EGFR family member expression was examined by Kaplan–Meier analysis (Figure 2). The median follow-up for all patients was 5.16 years (range, 0.58–11.08 years). Among the 63 patients, 11 patients (17.5%) had relapses of endometrial cancer at the time of last follow-up and 12 patients (19.0%) died. When HER-2 staining scores were used as cutoff points to stratify patients into two groups (see Materials and Methods), the progression-free survival (PFS) for low (score 0 or 1) and high (score 2 or 3) HER-2 expression was 91.9 and 69.2%, respectively (P=0.016). The overall survival (OS) for low and high HER-2 expression was 89.2 and 69.2%, respectively (P=0.044). Thus, high HER-2 expression was a factor that negatively influenced PFS and OS rates by univariate analysis. Epidermal growth factor receptor and HER-4 expression levels were not factors that affected PFS or OS by univariate analysis (Supplementary Figure 1). When other known variables for prognosis of endometrial cancer, including FIGO stage, pathological grade and myometrial invasion, were included in a Cox proportional hazard analysis for relapse-free survival, HER-2 expression (hazard ratio 5.31, P=0.0180) and FIGO stage were identified as independent predictive factors of patient survival (Table 5).


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)

Kaplan–Meier survival curves of 63 patients with endometrial cancer in relation to HER-2 expression. (A) Relapse-free survival (B) Overall survival.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Kaplan–Meier survival curves of 63 patients with endometrial cancer in relation to HER-2 expression. (A) Relapse-free survival (B) Overall survival.
Mentions: Next, the survival impact of EGFR family member expression was examined by Kaplan–Meier analysis (Figure 2). The median follow-up for all patients was 5.16 years (range, 0.58–11.08 years). Among the 63 patients, 11 patients (17.5%) had relapses of endometrial cancer at the time of last follow-up and 12 patients (19.0%) died. When HER-2 staining scores were used as cutoff points to stratify patients into two groups (see Materials and Methods), the progression-free survival (PFS) for low (score 0 or 1) and high (score 2 or 3) HER-2 expression was 91.9 and 69.2%, respectively (P=0.016). The overall survival (OS) for low and high HER-2 expression was 89.2 and 69.2%, respectively (P=0.044). Thus, high HER-2 expression was a factor that negatively influenced PFS and OS rates by univariate analysis. Epidermal growth factor receptor and HER-4 expression levels were not factors that affected PFS or OS by univariate analysis (Supplementary Figure 1). When other known variables for prognosis of endometrial cancer, including FIGO stage, pathological grade and myometrial invasion, were included in a Cox proportional hazard analysis for relapse-free survival, HER-2 expression (hazard ratio 5.31, P=0.0180) and FIGO stage were identified as independent predictive factors of patient survival (Table 5).

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