Breast cancer is the most common type of cancer and the most common cause of cancer-related mortality among women worldwide. There is currently no cure for breast cancer and thus a greater understanding of the underlying biology of breast cancer will identify molecular targets and allow for the development of novel therapeutics. Cancer cells exhibit altered metabolism, characterized by increased glucose uptake and increased glycolysis under aerobic condition, a process known as Warburg effect. The exact molecular mechanisms underlying cancers dependency on metabolic pathways is unclear. Regulation of proteins by O- GlcNAcylation, post-translational modifications, is a reversible process that depends on glucose availability and is a powerful mechanism to regulate protein function. In this proposal, we will elucidate the mechanisms of how the nutrient sensor O-GlcNAc transferase (OGT), the enzyme responsible for catalyzing addition of O-GlcNAc to proteins, regulates cancer cell metabolism and survival stress signaling. Preliminary data suggests that O- GlcNAcylation regulates cancer metabolism via regulation of HIF-1? in a pVHL-dependent manner. Thus, we hypothesize that O-GlcNAcylation regulates cancer cell metabolism and survival stress signaling through VHL- dependent stabilization of HIF-1?.
In Aim #1, we will determine whether O-GlcNAcylation regulation of cancer cell survival requires ER stress and HIF-1? pathways.
In Aim #2 we will determine how alterations in O- GlcNAc regulate the tumor suppressor VHL protein and determine its contribution to O-GlcNAc-mediated regulation on cancer cell survival metabolism and survival in vitro and in vivo. These studies will further our understanding of how metabolic reprogramming in cancer cells connects at the molecular level to survival stress pathways and identify novel anticancer pathways.

Public Health Relevance

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. Approximately 50% of all patients with breast cancer become unresponsive to current therapies thus newer therapies must be identified to treat breast cancer patients. The proposed study will test whether targeting an enzyme (OGT) can alter nutrient pathways to induce stress and selectively kill cancer cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vallejo-Estrada, Yolanda
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Drexel University
Schools of Medicine
United States
Zip Code
Sodi, V L; Bacigalupa, Z A; Ferrer, C M et al. (2018) Nutrient sensor O-GlcNAc transferase controls cancer lipid metabolism via SREBP-1 regulation. Oncogene 37:924-934
Ferrer, C M; Lu, T Y; Bacigalupa, Z A et al. (2017) O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway. Oncogene 36:559-569
Ferrer, Christina M; Sodi, Valerie L; Reginato, Mauricio J (2016) O-GlcNAcylation in Cancer Biology: Linking Metabolism and Signaling. J Mol Biol 428:3282-3294
Ferrer, Christina M; Lynch, Thomas P; Sodi, Valerie L et al. (2014) O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway. Mol Cell 54:820-31
Ferrer, Christina M; Reginato, Mauricio J (2014) Sticking to sugars at the metastatic site: sialyltransferase ST6GalNAc2 acts as a breast cancer metastasis suppressor. Cancer Discov 4:275-7