Prognostic significance of phosphorylated P38 mitogen‐activated protein kinase and HER‐2 expression in lymph node‐positive breast carcinoma

Esteva, Francisco J.; Şahin, Ayşegül; Smith, Terry L.; Yang, Ying; Pusztai, Lajos; Nahta, Rita; Buchholz, Thomas A.; Buzdar, Aman U.; Hortobágyi, Gabriel N.; Bacus, Sarah

doi:10.1002/cncr.11940

Cited by 103 publications

(77 citation statements)

References 34 publications

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“…Although several antibodies are now commercially available to stain Ki-67, anti-MIB-1 is the most frequently used in recent studies (Urruticoechea et al, 2005). In our meta-analysis, antibodies other than anti-MIB-1 and anti-Ki-67 were included, such as anti-Ki-S5 (Rudolph et al, 1999a;Esteva et al, 2004) and anti-Ki-S11 (Rudolph Figure 1 Results of the meta-analysis with all evaluable studies for DFS. A hazard ratio (HR)41 implies a worse DFS for the group with increased Ki-67.…”

Section: Discussionmentioning

confidence: 99%

“…Different antibodies were used through all trials: anti-Ki-67 was used in 24 studies (52.1%), anti-MIB-1 in 24 studies (52.1%), both antibodies were performed in five studies (Keshgegian and Cnaan, 1995;Veronese et al, 1995;Bevilacqua et al, 1996;Querzoli et al, 1996;Billgren et al, 2002), anti-Ki-S5 in two studies (Rudolph et al, 1999a;Esteva et al, 2004) and anti-Ki-S11 in one study (Rudolph et al, 1999b). The different cut-off values used were those of the authors (range: 3.5 -34%).…”

Section: Characteristics Of the Studiesmentioning

confidence: 99%

“…Out of the 38 evaluable studies for DFS (10 954 patients), subgroup analysis was possible in 15 studies with node-negative patients (3370 patients) (Sahin et al, 1991;Weikel et al, 1991Weikel et al, , 1995Gaglia et al, 1993;Bevilacqua et al, 1996;Brown et al, 1996;Pierga et al, 1996;Railo et al, 1997;Jansen et al, 1998;Clahsen et al, 1999;Harbeck et al, 1999;Rudolph et al, 1999a;Billgren et al, 2002;Trihia et al, 2003;Erdem et al, 2005), in eight with node-positive patients (1430 patients) (Weikel et al, 1991Gaglia et al, 1993;Pierga et al, 1996;Jansen et al, 1998;Billgren et al, 2002;Trihia et al, 2003;Esteva et al, 2004) and in six with untreated nodenegative patients (736 patients) (Sahin et al, 1991;Weikel et al, 1991;Bevilacqua et al, 1996;Railo et al, 1997;Jansen et al, 1998;Harbeck et al, 1999). Regarding OS (9472 patients), of all 35 studies, subgroup analysis was possible in nine studies with nodenegative patients (1996 patients) (Jensen et al, 1995;Weikel et al, 1995;Bevilacqua et al, 1996;Brown et al, 1996;Domagala et al, 1996;Fresno et al, 1997;Rudolph et al, 1999a;Trihia et al, 2003;Erdem et al, 2005), in four with node-positive patients (857 patients) Domagala et...…”

Section: Characteristics Of the Studiesmentioning

confidence: 99%

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Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients

et al. 2007

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The Ki-67 antigen is used to evaluate the proliferative activity of breast cancer (BC); however, Ki-67's role as a prognostic marker in BC is still undefined. In order to better define the prognostic value of Ki-67/MIB-1, we performed a meta-analysis of studies that evaluated the impact of Ki-67/MIB-1 on disease-free survival (DFS) and/or on overall survival (OS) in early BC. Sixty-eight studies were identified and 46 studies including 12 155 patients were evaluable for our meta-analysis; 38 studies were evaluable for the aggregation of results for DFS, and 35 studies for OS. Patients were considered to present positive tumours for the expression of Ki-67/MIB-1 according to the cut-off points defined by the authors. Ki-67/MIB-1 positivity is associated with higher probability of relapse in all patients (HR ¼ 1.93 (95% confidence interval (CI): 1.74 -2.14); Po0.001), in node-negative patients (HR ¼ 2.31 (95% CI: 1.83 -2.92); Po0.001) and in node-positive patients (HR ¼ 1.59 (95% CI: 1.35 -1.87); Po0.001). Furthermore, Ki-67/MIB-1 positivity is associated with worse survival in all patients (HR ¼ 1.95 (95% CI: 1.70 -2.24; Po0.001)), node-negative patients (HR ¼ 2.54 (95% CI: 1.65 -3.91); Po0.001) and node-positive patients (HR ¼ 2.33 (95% CI: 1.83 -2.95); Po0.001). Our meta-analysis suggests that Ki-67/ MIB-1 positivity confers a higher risk of relapse and a worse survival in patients with early BC.

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Section: Discussionmentioning

confidence: 99%

Section: Characteristics Of the Studiesmentioning

confidence: 99%

Section: Characteristics Of the Studiesmentioning

confidence: 99%

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Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients

et al. 2007

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“…7,8 However, enhanced p38 phosphorylation also correlates with poor prognosis in some patients with breast cancer and hepatocellular carcinoma. 9,10 Similarly, overexpression or activation of p38MAPK has been reported in lymphomas, thyroid neoplasms and human lung tumours. [11][12][13] In addition, inhibition of p38MAPK activity enhances apoptosis and cell sensitivity during administration of chemotherapy drugs.…”

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confidence: 83%

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

et al. 2016

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The stress-induced p38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in multiple physiological processes, including cancer. In turn, p38MAPK phosphorylation at Thr180 and Tyr182 is a key regulatory mechanism for its activation and functions. Here we show that this mechanism is actively regulated through isomerisation of Pro224. Different cyclophilins can isomerise this proline residue and modulate the ability of upstream kinases to phosphorylate Thr180 and Tyr182. In vivo mutation of Pro224 to Ile in endogenous p38MAPK significantly reduced its phosphorylation and activity. This resulted in attenuation of p38MAPK signalling, which in turn caused an enhanced apoptosis and sensitivity to a DNA-damaging drug, cisplatin. We further found a reduction in size and number of lesions in homozygous mice carrying the p38MAPK P224I substitution in a K-ras model of lung tumorigenesis. We propose that cyclophilin-dependent isomerisation of p38MAPK is an important novel mechanism in regulating p38MAPK phosphorylation and functions. Thus, inhibition of this process, including with drugs that are in clinical trials, may improve the efficacy of current anti-cancer therapeutic regimes.

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“…Activation of both JNK and p38 has been reported in breast carcinoma, 12 metastatic serous ovarian carcinoma 13 and in gastric cancer 14 whereas activation of JNK and p38 alone has been reported in poorly differentiated liver tumors 15 and in prostate cancer, 16 respectively. A correlation between activated JNK and early stages of nonsmall-cell lung cancers has been described.…”

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confidence: 99%

Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

2006

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Signaling pathways regulating cell proliferation and survival have become attractive targets for anticancer strategies. In the present study, we analyzed by immunohistochemistry, a panel of benign nevi, superficial spreading and nodular primary melanomas and metastases for expression of activated p38/mitogen-activated protein kinase (p-p38) and c-jun N-terminal kinase (JNK) (p-JNK) and correlated the findings with known prognostic variables. Twenty-five and 35% of the primaries and 9 and 25% of the metastases expressed variable levels of p-p38 and p-JNK, respectively. In benign nevi, 73.5% expressed p-JNK and 7% expressed p-p38. For patients with superficial spreading melanomas, high level of cytoplasmic p-JNK was associated with thicker tumors (P ¼ 0.017) and shorter disease-free survival (P ¼ 0.003) as well as with markers of cell proliferation (cyclin A (P ¼ 0.017) and p21 (P ¼ 0.021)). In nodular melanomas, nuclear p-p38 was associated with Ki-67 (P ¼ 0.012), but neither cytoplasmic nor nuclear localized p-p38 was associated with disease outcome. Of note, in superficial spreading melanomas, a positive correlation between cytoplasmic p-JNK and cytoplasmic p-extracellular signal-regulated kinase ERK1/2 (P ¼ 0.005) and p-p38 (P ¼ 0.003) was observed. Likewise, p-p38 in cytoplasm was positively associated with cytoplasmic p-ERK1/2 (Po0.0005) and p-Akt (P ¼ 0.047). In contrast, except for a positive correlation between nuclear p-p38 and membranous p-TrkA (P ¼ 0.02), no correlation between the activation status of the different signaling pathways was observed in nodular melanomas. In conclusion, our results suggest that in benign nevi activated JNK may have a role in restricting uncontrolled cell proliferation or survival. However, during tumor progression, activation of JNK is associated with cell proliferation and shorter relapse-free period for patients with superficial spreading melanomas, suggesting that the JNK activation status could be a marker for clinical outcome in at least a subgroup of malignant melanoma. In contrast, activation of p38 seems to play a less important role in development and progression of malignant melanomas.

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Prognostic significance of phosphorylated P38 mitogen‐activated protein kinase and HER‐2 expression in lymph node‐positive breast carcinoma

Cited by 103 publications

References 34 publications

Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients

Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma

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