Malorni, Luca (2009) Breast cancer endocrine resistance: stress-related kinase pathways and the role of JNK/AP-1. [Tesi di dottorato] (Unpublished)

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Abstract

Background: Endocrine treatment is the mainstay therapy for estrogen receptor positive (ER+) breast cancer patients. Although effective in many cases, some patients do not respond to endocrine therapy and display de novo resistance, while a substantial fraction of initially responding patients ultimately acquires resistance. Understanding the complex biology underlying resistance is critical for the development of new therapeutic strategies for these patients. Methods and results: We performed expression array analysis of xenograft tumors from two well characterized models of endocrine resistance that recapitulate relevant clinical scenarios: MCF7, and its HER2 overexpressing derivative model, MCF7/HER2-18. We developed gene classifiers representing differentially regulated transcripts at the time of resistance and analyzed them using publicly available datasets from breast cancer cell lines and breast cancer patients. We found that resistant tumors undergo complex phenotypic changes at time of resistance. Resistant tumors showed upregulation of a set of genes that is overexpressed in ER-/HER2+ human tumors, and showed downregulation of classical ER-dependent genes. Therefore, at time of resistance, ER signaling appears to be effectively impaired by endocrine treatment while alternative pathways are activated, sustaining endocrine resistant growth. Evidence from the expression array data and from other studies in our group suggests that the stress-related kinase pathways JNK/AP-1 and p38 MAPK are activated at time of resistance. Therefore, we studied these pathways in greater detail. To investigate the role of JNK/AP-1 inhibition, we used MCF7 cells stably transfected with an inducible, dominant negative (DN) cJun. Two clones were studied in vitro and grown as xenografts in mice treated with endocrine therapy, either in the presence or absence of DN cJun. Expression of DN cJun in both clones potentiated the effect of endocrine treatment both in vitro and in vivo. We observed that endocrine treatment induces mainly a cytostatic effect when used on its own, but elicits dramatic cytotoxicity when used concomitantly with AP-1 blockade. Tumors treated with endocrine therapy in combination with AP-1 inhibition responded significantly faster to treatment compared to control tumors. When the DN cJun was induced at time of endocrine resistance, we observed striking tumor response in all tumors, suggesting that AP-1 blockade can effectively reverse the resistant phenotype. To investigate the role of p38MAPK, we generated MCF7 clones stably expressing DN p38 in an inducible fashion. After validating the effectiveness of p38 pathway blockade in the clones, we studied the effect of such inhibition in combination with endocrine treatment. In vivo data from DNp38 xenografts suggest that p38 inhibition reduces tumor growth rate when tumors start to develop resistance, while surprisingly accelerating tumor growth in endocrine naïve tumors. Conclusions: Our data show that, when challenged with endocrine therapy, over time the molecular phenotypes of breast cancer may change, and that resistant tumors may rely on new, alternative escape pathways. We, for the first time, provide proof that stress-related kinase pathways such as JNK/AP-1 and p38 may participate in such alternative resistance mechanisms. Therefore, these pathways are promising therapeutic targets for endocrine resistant breast cancer. Further preclinical, as well as clinical, studies are warranted.

Item Type: Tesi di dottorato
Uncontrolled Keywords: Breast cancer, stress-related kinases, p38, AP-1, endocrine treatment
Depositing User: Francesca Migliorini
Date Deposited: 28 May 2010 10:27
Last Modified: 30 Apr 2014 19:39
URI: http://www.fedoa.unina.it/id/eprint/3947

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