Amplified in breast cancer regulates transcription and translation in breast cancer cells
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Date
2016
Authors
Ochnik, A.M.
Peterson, M.S.
Avdulov, S.V.
Oh, A.S.
Bitterman, P.B.
Yee, D.
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Journal article
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Neoplasia: An International Journal for Oncology Research, 2016; 18(2):100-110
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Abstract
Background - Control of mRNA translation is fundamentally altered in cancer. Insulin-like growth factor-I (IGF-I) signaling regulates key translation mediators to modulate protein synthesis (e.g. eIF4E, 4E-BP1, mTOR, and S6K1). Importantly the Amplified in Breast Cancer (AIB1) oncogene regulates transcription and is also a downstream mediator of IGF-I signaling.
Materials and methods - To determine if AIB1 also affects mRNA translation, we conducted gain and loss of AIB1 function experiments in estrogen receptor alpha (ERα)+ (MCF-7L) and ERα⁻ (MDA-MB-231, MDA-MB-435 and LCC6) breast cancer cells.
Results - AIB1 positively regulated IGF-I-induced mRNA translation in both ERα+and ERα⁻ cells. Formation of the eIF4E-4E-BP1 translational complex was altered in the AIB1 ERα+ and ERα⁻ knockdown cells, leading to a reduction in the eIF4E/4E-BP1and eIF4G/4E-BP1 ratios. In basal and IGF-I stimulated MCF-7and LCC6 cells, knockdown of AIB1 decreased the integrity of the cap-binding complex, reduced global IGF-I stimulated polyribosomal mRNA recruitment with a concomitant decrease in ten of the thirteen genes tested in polysome-bound mRNAs mapping to proliferation, cell cycle, survival, transcription,translation and ribosome biogenesis ontologies. Specifically, knockdown of AIB1 decreased ribosome-bound mRNA and steady-state protein levels of the transcription factors ERαand E2F1 in addition to reduced ribosome-bound mRNA of theribosome biogenesis factor BYSL in a cell-line specific manner to regulate mRNA translation.
Conclusion - The oncogenic transcription factor AIB1 has a novel role in the regulation of polyribosome recruitment and formation of the translational complex. Combinatorial therapies targeting IGF signaling and mRNA translation in AIB1 expressing breast cancers may have clinical benefit and warrants further investigation.
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Data source: Supplementary materials, http://www.sciencedirect.com/science/MiamiMultiMediaURL/1-s2.0-S1476558616000026/1-s2.0-S1476558616000026-mmc1.docx/306540/html/S1476558616000026/51c474565d683c4ffaf1dd26388f3abb/mmc1.docx
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2016 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)