Ting Zhuang

Bioscience and nutrition, Karolinska Institutet

Objective:Tamoxifen resistance leads to lethality ina substantial fraction of estrogen positive breast cancer patients. The aim ofthe study is to identify the effect of PAK4 on tamoxifen resistance in breastcancer cells. Method: western blot, Q-PCR, luciferase report assay,Chromatin immunoprecipitation, flow cytometry. Result: we show that highp21-activated kinase-4 (PAK4) expression was linked to poor patient outcome intamoxifen - treated breast cancer patients. Importantly, while PAK4 over expressioninhibited  tamoxifen-

responsivenessof MCF-7 human breast cancer cells, pharmacological treatment using the PAK4-inhibitorGNE-2861, strongly sensitized tamoxifen-resistant breast cancer cells MCF7-LCC2to tamoxifen. Mechanist

ically,we identified a regulatory feed-forward loop, where estrogenreceptor alpha(ERα) bound to the PAK4 promoter, thereby promoting PAK4expression, while PAK4in turn stabilized the ERα protein, activated ERαtranscriptional activity andERα target gene expression. Conclusion: In conclusion, pharmacological PAK4targeting can overcome tamoxifen resistance though blocking of PAK4-mediatedERα activation, indicating that PAK4 may be a suitable target for the developmentof novel therapy for tamoxifen resistant breast cancer.

KeyWords: PAK4 ER  breast cancer