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

• Published in: Neoplasia (New York, N.Y.) Vol. 18; no. 2; pp. 100 - 110
• Main Authors: Ochnik, Aleksandra M, Peterson, Mark S, Avdulov, Svetlana V, Oh, Annabell S, Bitterman, Peter B, Yee, Douglas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2016; Neoplasia Press; Elsevier
• Subjects: Adaptor Proteins, Signal Transducing - biosynthesis; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Estrogen Receptor alpha - genetics; Eukaryotic Initiation Factor-4E - biosynthesis; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Insulin-Like Growth Factor I - biosynthesis; Insulin-Like Growth Factor I - genetics; MCF-7 Cells; Nuclear Receptor Coactivator 3 - genetics; Oncology; Phosphoproteins - biosynthesis; Phosphorylation; Protein Biosynthesis; Ribosomal Protein S6 Kinases, 70-kDa - biosynthesis; Signal Transduction - genetics; TOR Serine-Threonine Kinases - biosynthesis; Mitogen activated protein kinase; IGF-I; Bystin; AIB1; IGF1R; Insulin-like growth factor-I; Mammalian target of rapamycin complex 1; TNBC; Triple negative breast cancer; eIF4E; Amplified in Breast Cancer 1; eIF4G; Eukaryotic translation initiation factor 4E; ERα; MAPK; BYSL; S6K1; Eukaryotic translation initiation factor 4 gamma; Ribosomal S6 kinase 1; Eukaryotic translation initiation factor 4E-binding protein 1; Human epidermal growth factor receptor 2; 4E-BP1; Estrogen receptor alpha; HER2; Type I IGF receptor; mTORC1
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1016/j.neo.2016.01.001

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.