Correlation of TLK1B in Elevation and Recurrence in Doxorubicin-Treated Breast Cancer Patients with High eIF4E Overexpression

Byrnes, Kerry; DeBenedetti, Arrigo; Holm, Neal; Luke, Jay; Nunez, Jade; Chu, Quyen D.; Meschonat, Carol; Abreo, Fleurette; Johnson, Lester W.; Li, Benjamin D.L.

doi:10.1016/j.jamcollsurg.2007.02.027

Cited by 21 publications

(15 citation statements)

References 23 publications

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“…43 TLKs Are Targets for Therapeutic Intervention. The TLKs are becoming the center of much attention for their role in DSB repair 4,19,44 and their potential contribution to cancers refractory to XRT or RMT, including cholangiocarcinoma, 45 BCA, 8 and CaP. 11 Note, however, that probably most technologies directed at globally reducing the expression of TLKs are unlikely to result in effective and safe therapies.…”

Section: Discussionmentioning

confidence: 99%

“…The past few years have witnessed significant advances in understanding the roles of TLKs in the DDR 7 and in DSB repair 4 as well as their clinical relevance. In BCA, elevated expression of the TLK1B splice form is found in approximately 30% of the patients and often corresponds to poor response to XRT and doxorubicin (doxo), 8 presumably due to efficient DSB repair in the tumor cells. We postulated that its expression could serve as a marker for prognosis as well as a target for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

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Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy

et al. 2013

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The Tousled-like kinases (TLKs) are involved in chromatin assembly, DNA repair, and transcription. Two TLK genes exist in humans, and their expression is often dysregulated in cancer. TLKs phosphorylate Asf1 and Rad9, regulating double-strand break (DSB) repair and the DNA damage response (DDR). TLKs maintain genomic stability and are important therapeutic intervention targets. We identified specific inhibitors of TLKs from several compound libraries, some of which belong to the family of phenothiazine antipsychotics. The inhibitors prevented the TLK-mediated phosphorylation of Rad9(S328) and impaired checkpoint recovery and DSB repair. The inhibitor thioridazine (THD) potentiated tumor killing with chemotherapy and also had activity alone. Staining for γ-H2AX revealed few positive cells in untreated tumors, but large numbers in mice treated with low doxorubicin or THD alone, possibly the result of the accumulation of DSBs that are not promptly repaired as they may occur in the harsh tumor growth environment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Phenothiazine Inhibitors of TLKs Affect Double-Strand Break Repair and DNA Damage Response Recovery and Potentiate Tumor Killing with Radiomimetic Therapy

et al. 2013

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“…The past few years have witnessed significant advances in understanding the roles of TLKs in the DDR [66] and in direct repair of DSBs [9], as well as their clinical relevance. In BCA, elevated expression of the TLK1B splice form is found in ~30% of the patients [67] and often corresponds to poor response to XRT [68] and doxorubicin [67], presumably due to efficient repair of DSBs in the tumor cells. We postulated that its expression could serve as a marker for prognosis as well as a target for therapeutic intervention.…”

Section: Tlks In Man As Guardians Of Genome Stability and Their mentioning

confidence: 99%

The Tousled-Like Kinases as Guardians of Genome Integrity

Benedetti

2012

ISRN Molecular Biology

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The Tousled-like kinases (TLKs) function in processes of chromatin assembly, including replication, transcription, repair, and chromosome segregation. TLKs interact specifically (and phosphorylate) with the chromatin assembly factor Asf1, a histone H3-H4 chaperone, histone H3 itself at Ser10, and also Rad9, a key protein involved in DNA repair and cell cycle signaling following DNA damage. These interactions are believed to be responsible for the action of TLKs in double-stranded break repair and radioprotection and also in the propagation of the DNA damage response. Hence, I propose that TLKs play key roles in maintenance of genome integrity in many organisms of both kingdoms. In this paper, I highlight key issues of the known roles of these proteins, particularly in the context of DNA repair (IR and UV), their possible relevance to genome integrity and cancer development, and as possible targets for intervention in cancer management.

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“…The suspected mechanism of action is chromatin remodeling caused by histone H3 phosphorylation [16]. This is important because doxorubicin, a commonly used therapy for breast cancer, functions by damaging DNA via double-stranded breaks [17]. In breast cancer patients, Byrnes and colleagues reported that a high TLK1B overexpression not only correlates with eIF4E overexpression, but also is associated with an increased risk for recurrence in patients receiving doxorubicin-based therapy [17].…”

Section: Introductionmentioning

confidence: 99%