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- W2492113863 abstract "Activating mutations in Ras GTPases frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the Ras/Raf/MEK/ERK pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. Several studies have shown that signaling through the Ras/Raf/MEK/ERK pathway can be influenced by Pak1 kinase, a downstream effector of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase. In addition, it has been shown that Pak1 is amplified in several human cancer types, including 25-30% of breast tumor samples and cancer cell lines, and that its kinase activity is necessary for Ras mediated transformation. In this work, we performed a comparative gene profiling study in order to identify differentially regulated genes between wild-type and Pak1 deficient mouse and human breast cancer cells. Several genes involved in the Fanconi Anemia/BRCA pathway - a DNA-damage response signaling pathway that is essential for repairing DNA interstrand cross-links induced by DNA-damaging agents like cisplatin and doxorubicin - were down-regulated in Pak1 deficient cells. The reduced expression of FANCD2 and FANCI was confirmed by qPCR and western blot in Pak1-depleted human breast cancer cells with or without 11q13 amplification. Interestingly, the depletion or chemical inhibition of Pak1 in 11q13 amplified breast cancer cells treated with cisplatin, compromised the ability of these cells to repair DNA by homologous recombination, induced cell cycle arrest, promoted apoptosis and resulted in reduced colony formation. In contrast, the inhibition or depletion of Pak1 had little effect on these cellular processes in Pak1-non-amplified breast cancer cells. Because reduced Pak1 activity impaired Fanconi Anemia/BRCA signaling and consequently, repair by homologous recombination, inhibition of Pak1 represents a plausible strategy for expanding the utility of DNA-damaging treatments to Fanconi Anemia/BRCA-proficient 11q13 amplified breast cancers. Citation Format: Luis E. Arias-Romero, Olga Villamar-Cruz, Jonathan Chernoff. Pak1 kinase inhibition sensitizes 11q13 amplified breast cancer cells to platinum based chemotherapy via downregulation of Fanconi anemia genes. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A02. doi: 10.1158/1557-3125.RASONC14-A02" @default.
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- W2492113863 date "2014-12-01" @default.
- W2492113863 modified "2023-09-25" @default.
- W2492113863 title "Abstract A02: Pak1 kinase inhibition sensitizes 11q13 amplified breast cancer cells to platinum based chemotherapy via downregulation of Fanconi anemia genes" @default.
- W2492113863 doi "https://doi.org/10.1158/1557-3125.rasonc14-a02" @default.
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