Cyclin e associates with the lipogenic enzyme ATP-citrate lyase to enable malignant growth of breast cancer cells

Kimberly S. Lucenay, Iman Doostan, Cansu Karakas, Tuyen Bui, Zhiyong Ding, Gordon Mills, Kelly K. Hunt, Khandan Keyomarsi

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Cyclin E is altered in nearly a third of invasive breast cancers where it is a powerful independent predictor of survival in women with stage I-III disease. Full-length cyclin E is post-translationally cleaved into low molecular weight (LMW-E) isoforms, which are tumor-specific and accumulate in the cytoplasm because they lack a nuclear localization sequence. We hypothesized that aberrant localization of cytosolic LMW-Eisoforms alters target binding and activation ultimately contributing to LMW-E-induced tumorigenicity. To address this hypothesis, we used a retrovirus-based protein complementation assay to find LMW-E binding proteins in breast cancer, identifying ATP-citrate lyase (ACLY), an enzyme in the de novo lipogenesis pathway, as a novel LMW-E-interacting protein in the cytoplasm. LMW-E upregulated ACLY enzymatic activity, subsequently increasing lipid droplet formation, thereby providing cells with essential building blocks to support growth. ACLY was also required for LMW-E-mediated transformation, migration, and invasion of breast cancer cells in vitro along with tumor growth in vivo. In clinical specimens of breast cancer, the absence of LMW-E and low expression of adipophilin (PLIN2), a marker of lipid droplet formation, associated with favorable prognosis, whereas overexpression of both proteins correlated with a markedly worse prognosis. Taken together, our findings establish a novel relationship between LMW-E isoforms of cyclin E and aberrant lipid metabolism pathways in breast cancer tumorigenesis, warranting further investigation in additional malignancies exhibiting their expression. Cancer Res; 76(8); 2406-18.

Original languageEnglish (US)
Pages (from-to)2406-2418
Number of pages13
JournalCancer Research
Volume76
Issue number8
DOIs
Publication statusPublished - Apr 15 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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