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

28 Citations (Scopus)

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
StatePublished - Apr 15 2016
Externally publishedYes

Fingerprint

ATP Citrate (pro-S)-Lyase
Cyclins
Molecular Weight
Breast Neoplasms
Enzymes
Growth
Cyclin E
Neoplasms
Protein Isoforms
Cytoplasm
Retroviridae Proteins
Lipogenesis
Lipid Metabolism
Carrier Proteins
Carcinogenesis
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cyclin e associates with the lipogenic enzyme ATP-citrate lyase to enable malignant growth of breast cancer cells. / Lucenay, Kimberly S.; Doostan, Iman; Karakas, Cansu; Bui, Tuyen; Ding, Zhiyong; Mills, Gordon; Hunt, Kelly K.; Keyomarsi, Khandan.

In: Cancer Research, Vol. 76, No. 8, 15.04.2016, p. 2406-2418.

Research output: Contribution to journalArticle

Lucenay, Kimberly S. ; Doostan, Iman ; Karakas, Cansu ; Bui, Tuyen ; Ding, Zhiyong ; Mills, Gordon ; Hunt, Kelly K. ; Keyomarsi, Khandan. / Cyclin e associates with the lipogenic enzyme ATP-citrate lyase to enable malignant growth of breast cancer cells. In: Cancer Research. 2016 ; Vol. 76, No. 8. pp. 2406-2418.
@article{d10c7135fe5147bb9c6bf5d55a4526c0,
title = "Cyclin e associates with the lipogenic enzyme ATP-citrate lyase to enable malignant growth of breast cancer cells",
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.",
author = "Lucenay, {Kimberly S.} and Iman Doostan and Cansu Karakas and Tuyen Bui and Zhiyong Ding and Gordon Mills and Hunt, {Kelly K.} and Khandan Keyomarsi",
year = "2016",
month = "4",
day = "15",
doi = "10.1158/0008-5472.CAN-15-1646",
language = "English (US)",
volume = "76",
pages = "2406--2418",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Cyclin e associates with the lipogenic enzyme ATP-citrate lyase to enable malignant growth of breast cancer cells

AU - Lucenay, Kimberly S.

AU - Doostan, Iman

AU - Karakas, Cansu

AU - Bui, Tuyen

AU - Ding, Zhiyong

AU - Mills, Gordon

AU - Hunt, Kelly K.

AU - Keyomarsi, Khandan

PY - 2016/4/15

Y1 - 2016/4/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84970971279&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84970971279&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-15-1646

DO - 10.1158/0008-5472.CAN-15-1646

M3 - Article

C2 - 26928812

AN - SCOPUS:84970971279

VL - 76

SP - 2406

EP - 2418

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 8

ER -