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Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate.

ABSTRACT: Breast carcinoma (BC) remains one of the most serious health problems. It is a heterogeneous entity, and mainly classified according to receptor status for estrogen (ER), progesterone (PR) and egf (HER2/Neu), as well as the proliferation marker ki67. Gene expression in eukaryotes is regulated at the level of both gene transcription and translation, where eukaryotic initiation factors (eIFs) are key regulators of protein biosynthesis. Aberrant translation results in an altered cellular proteome, and this clearly effects cell growth supporting tumorigenesis. The relationship between various eIFs and BC entities, as well as the related regulatory mechanisms, has meanwhile become a focus of scientific interest. Here, we give an overview on the current research state of eIF function, focusing on BC.

SUBMITTER: Chen Q

PROVIDER: S-EPMC7409344 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate.

Chen Qin Q Yang Bo B Nass Norbert N Schatz Christoph C Haybaeck Johannes J

Cancers 20200721 7

Breast carcinoma (BC) remains one of the most serious health problems. It is a heterogeneous entity, and mainly classified according to receptor status for estrogen (ER), progesterone (PR) and egf (HER2/Neu), as well as the proliferation marker ki67. Gene expression in eukaryotes is regulated at the level of both gene transcription and translation, where eukaryotic initiation factors (eIFs) are key regulators of protein biosynthesis. Aberrant translation results in an altered cellular proteome, ...[more]

PMID: 32708122

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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

Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate.

Publications

Impact of Eukaryotic Translation Initiation Factors on Breast Cancer: Still Much to Investigate.

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