The stressactivated mitogenactivated protein kinases JNK and p38

As stated above, significant influences on ER and AP-1 signaling may also occur following phosphorylation of the SAPK members Jun kinase (JNK) and p38. While the endpoints of such signaling are likely to be as diverse as for ERK1/2 MAP kinase, as stated above, significant in vitro associations with negative growth regulation in breast cancer cells have been reported for JNK and p38.16,17,53 If represented in clinical breast cancer, therefore, JNK and p38 signaling would perhaps be predicted to substantially impact on patient prognosis and endocrine response in a manner diametrically opposed to pMAP kinase. Again, our studies immunocytochemically employing phospho-specific antibodies for JNK and p38 in clinical breast cancer have proved interesting in this regard.128 We noted that nuclear activation of JNK or p38 was not uncommon within clinical breast cancer (Figure 10.3). Significant expression of activated p38 and JNK appeared to confer an advantage on duration of survival and endocrine response, an observation in marked contrast to our observations with pMAP kinase. This was particularly apparent within tumors where the relationship between response to endocrine therapy and elevated pMAP kinase activation proved imperfect. Thus, approximately 15% of objective respon-ders with elevated pMAP kinase activation in their tumors coexpressed activated JNK or p38.128 These data suggest that activation of p38 and JNK may serve as a "counterbalance" in some breast cancers for the undesirable positive influences of pMAP kinase, thereby facilitating the growth inhibitory activity of endocrine agents.129

However, our observations with SAPKs in clinical breast cancer remain controversial. Paradoxically, increases in both p38 and JNK activity have also been associated with disease progression with activity elevated in effusions compared with primary tumors and lymph node metastases, and p38 relating to reduced overall survival130 and to shortened progression-free survival in lymph node-positive breast cancer.131 Moreover, our preliminary studies also noted some increases in activity of both JNK and p38 at the time of disease relapse of ER-positive endocrine responsive clinical breast cancer when treated with tamoxi-fen. Increased JNK activity has similarly been measured by others in acquired tamoxifen-resistant clinical breast cancer,132,133 while Gutierrez et al85 reported that some ER-positive, acquired tamoxifen-resistant patients (and xenografts) show increased p38 activation alongside modest gains in HER2 amplification. The latter study also revealed strong correlations between ER, p38 and ERK, data cumulatively implying crosstalk between ER, HER2, p38 (and ERK) which contributes to tamoxifen-resistant growth. Indeed, evidence of such crosstalk has been demonstrated in a xenograft model of acquired tamoxifen-resis-tant MCF-7 cells.85 It is feasible that a positive role for stress-activated kinases such as p38 in driving clinical-resistant disease may occur via their regulation of AP-1 activity, which can also be increased in such material122,132,133 or perhaps via activation of ER or its coactivators to enhance agonism of the tamoxifen-ER



The clinical data described above regarding activation of ERK1/2 MAP kinase and the SAPKs JNK and p38 suggest that these signaling elements have prognostic potential. However, more definitive studies with greater access to appropriate clinical sample sets, including samples taken during response and at relapse, are required to confirm these initial findings. It should also be noted that this data may also have important therapeutic implications. For example, breast tumors derived from patients exhibiting de novo endocrine resistance and an unfavorable prognosis may be candidates for challenge with pharmacological agents disruptive of ERK1/2 MAP kinase signaling. The recent development of inhibitors of MEK1 activation,134,135 as well as further agents disruptive of the upstream erbB signaling network, notably including tyrosine kinase inhibitors such as "ZD1839/Iressa" and targeted antibody therapies such as Herceptin,136 could be valuable additions to the pharmacological armory appropriate in future management of the disease. Moreover, our observation that coexpression of activated JNK or p38 in clinical breast cancer is associated with a perturbation of the relationship between phos-phorylated ERK 1/2 MAP kinase and poor outlook may ultimately provide some rationale for therapeutic manipulation of SAPKs to dampen any undesirable impact of elevated ERK 1/2 MAP kinase signaling. However, it should also be noted that the identification of a role for p38 and JNK in acquired tamoxifen resistance85,132,133 also identifies them, alongside ERK1/2 MAP kinase, as potential therapeutic targets for the treatment of this condition.


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Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

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