Atp-Citrate Lyase Links Cyclin E to Cellular Metabolism In Breast Cancer

<p>Cyclin E is altered or overexpressed in approximately one-third of tumors from patients with invasive breast cancer and is a powerful independent predictor for survival in women with stage I-III breast cancer. Full-length cyclin E (EL) is post-translationally cleaved into two low-molecular-weight isoforms, LMW-E (T1) and LMW-E (T2). LMW-E have been shown to exhibit greater binding affinity for cyclin-dependent kinase 2 (CDK2) , cyclin dependent kinase inhibitors (CKIs), p21 and p27, but are resistant to p21 and p27 inhibition. In addition, transgenic mice expressing LMW-E have increased mammary tumor development and metastasis compared to EL transgenic mice. Therefore, LMW-E are more aggressive in cell cycle abrogation and mammary tumor development. The LMW-E isoforms are tumor specific and accumulate in the cytoplasm due to lack of a nuclear localization sequence (NLS). Therefore, we hypothesized that aberrant localization of LMW-E isoforms leads to molecular events that ultimately contribute to LMW-E breast cancer tumorigenicity. To address this hypothesis, we used a retrovirus-based protein complementation assay (RePCA) to identify LMW-E (T1) protein-protein interactions in breast cancer. Using this methodology, we found ATP-citrate lyase (ACLY) as a novel interacting protein of LMW-E (T1) in the cytoplasm. ACLY is a 125kDa homotetrameric enzyme that catalyzes cytoplasmic citrate to acetyl-CoA and oxaloacetate in the <em>de novo</em> lipogenesis pathway. End products of this pathway consist of complex fatty acids that fuel membrane production of highly proliferating cells and lipid-based post-translational modifications that mediate protein-protein interactions. Additionally, we found that LMW-E upregulates ACLY enzymatic activity which leads to lipid droplet formation; thereby providing cells with essential building blocks to support growth. ACLY is also required for LMW-E mediated transformation, migration and invasion <em>in vitro</em>, as well as tumor growth <em>in vivo</em>. Taken together these data suggest a novel interplay between LMW-E and ACLY and how metabolic pathways and the cell cycle are linked in breast cancer tumorigenesis.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2015

Author dc:creator

• Lucenay, Kim

Contributors dc:contributor

• Khandan Keyomarsi, Ph.D.
• Jill Schumacher, Ph.D.
• Wei Zhang, Ph.D.

• Breast cancer Low molecular weight cyclin E ATP-citrate lyase Retrovirus-based protein complementation assay Lipid droplets
• Biology
• Cancer Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/594

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1636