Amplified in Breast Cancer Regulates Transcription and Translation in Breast Cancer Cells

Aleksandra M. Ochnik, Mark S. Peterson, Svetlana V. Avdulov, Annabell S. Oh, Peter B. Bitterman, Douglas Yee

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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-BP1 and eIF4G/4E-BP1 ratios. In basal and IGF-I stimulated MCF-7 and 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 ERα and E2F1 in addition to reduced ribosome-bound mRNA of the ribosome 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.

Original languageEnglish (US)
Pages (from-to)100-110
Number of pages11
JournalNeoplasia (United States)
Volume18
Issue number2
DOIs
StatePublished - 2016

Bibliographical note

Funding Information:
This work was supported by funding provided by a Susan G. Komen for the Cure Post-doctoral Research and Training Post-doctoral Fellowship KG101465 (ASO and AMO), Komen for the Cure, SAC110039 (DY), NIH R01CA CA074285 (DY), and Cancer Center Support Grant P30 CA 077598. We would like to acknowledge Dr. Christopher Chien for the preparation of the AIB1 knockdown breast cancer cell-lines used in the studies detailed in this manuscript. We acknowledge V. Polunonvsky for providing the pCDNA3-renilla-LUC-IRES-firefly-LUC vector and Dr. Karen Scott for assistance with generation of the plasmid sequence. Thank you to Dr. Scott Dehm and Luke Brand for reporter gene assay technical assistance undertaken for this manuscript.

Funding Information:
This work was supported by funding provided by a Susan G. Komen for the Cure Post-doctoral Research and Training Post-doctoral Fellowship KG101465 (ASO and AMO), Komen for the Cure, SAC110039 (DY), NIH R01CA CA074285 (DY), and Cancer Center Support Grant P30 CA 077598. We would like to acknowledge Dr. Christopher Chien for the preparation of the AIB1 knockdown breast cancer cell-lines used in the studies detailed in this manuscript. We acknowledge V. Polunonvsky for providing the pCDNA3-renilla-LUC-IRES-firefly-LUC vector and Dr. Karen Scott for assistance with generation of the plasmid sequence. Thank you to Dr. Scott Dehm and Luke Brand for reporter gene assay technical assistance undertaken for this manuscript.

Fingerprint Dive into the research topics of 'Amplified in Breast Cancer Regulates Transcription and Translation in Breast Cancer Cells'. Together they form a unique fingerprint.

Cite this