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Targeting translation initiation in breast cancer.

ABSTRACT: Over the past 20 years, a better understanding of cancer biology, screening for early detection, improved adjuvant treatment, and targeted therapies have decreased the rate of breast cancer deaths. However, resistance to treatment is common, and new approaches are needed. Deregulation of translation initiation is associated with the commencement and progression of cancer. Often, translation initiation factors are overexpressed and the related signaling pathways activated in human tumors. Recently, a significant number of inhibitors that target translation factors and pathways have become available. These inhibitors are being tested alone or in combination with chemotherapeutic agents in clinical trials. The results are varied, and it is not yet clear which drug treatments most effectively inhibit tumor growth. This review highlights the pathways and downstream effects of the activation of translation and discusses targeting the control of translation initiation as a therapeutic approach in cancer, focusing on breast cancer clinical trials.

SUBMITTER: Akcakanat A

PROVIDER: S-EPMC4705830 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Targeting translation initiation in breast cancer.

Akcakanat Argun A Hong David S DS Meric-Bernstam Funda F

Translation (Austin, Tex.) 20140429 1

Over the past 20 years, a better understanding of cancer biology, screening for early detection, improved adjuvant treatment, and targeted therapies have decreased the rate of breast cancer deaths. However, resistance to treatment is common, and new approaches are needed. Deregulation of translation initiation is associated with the commencement and progression of cancer. Often, translation initiation factors are overexpressed and the related signaling pathways activated in human tumors. Recentl ...[more]

PMID: 26779407

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Project description:Breast cancer stem cells (BCSCs) are intrinsically chemoresistant and capable of self-renewal. Following chemotherapy, patients can develop minimal residual disease due to BCSCs which can repopulate into a relapsed tumor. Therefore, it is imperative to co-target BCSCs along with the bulk tumor cells to achieve therapeutic success and prevent recurrence. So, it is vital to identify actionable molecular targets against both BCSCs and bulk tumor cells. Previous findings from our lab and others have demonstrated that inhibition of the emerging drug target eIF4A with Rocaglamide A (RocA) was efficacious against triple-negative breast cancer cells (TNBC). RocA specifically targets the pool of eIF4A bound to the oncogenic mRNAs that requires its helicase activity for their translation. This property enables specific targeting of tumor cells. The efficacy of RocA against BCSCs is unknown. In this study, we postulated that eIF4A could be a vulnerable node in BCSCs. In order to test this, we generated a paclitaxel-resistant TNBC cell line which demonstrated an elevated level of eIF4A along with increased levels of cancer stemness markers (ALDH activity and CD44), pluripotency transcription factors (SOX2, OCT4, and NANOG) and drug transporters (ABCB1, ABCG2, and ABCC1). Furthermore, genetic ablation of eIF4A resulted in reduced expression of ALDH1A1, pluripotency transcription factors and drug transporters. This pointed out that eIF4A is likely associated with selected set of proteins that are critical to BCSCs, and hence targeting eIF4A may eliminate BCSCs. Therefore, we isolated BCSCs from two TNBC cell lines: MDA-Bone-Un and SUM-159PT. Following RocA treatment, the self-renewal ability of the BCSCs was significantly reduced as determined by the efficiency of the formation of primary and secondary mammospheres. This was accompanied by a reduction in the levels of NANOG, OCT4, and drug transporters. Exposure to RocA also induced cell death of the BCSCs as evaluated by DRAQ7 and cell viability assays. RocA treatment induced apoptosis with increased levels of cleaved caspase-3. Overall, we identified that RocA is effective in targeting BCSCs, and eIF4A is an actionable molecular target in both BCSCs and bulk tumor cells. Therefore, anti-eIF4A inhibitors could potentially be combined synergistically with existing chemo-, radio- and/or immunotherapies.

Dataset Information

Targeting translation initiation in breast cancer.

Publications

Targeting translation initiation in breast cancer.

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