Date of Award

Summer 2020

Document Type

Open Access Thesis


Biomedical Engineering

First Advisor

Sajish Mathew


Breast cancer is one of the most commonly occurring cancers in women. 70% of breast cancer patients express ERα and are treated with tamoxifen (Tam), a drug that is used to directly target ERα. However, 20-30% of cancer patients develop a resistance to Tam. This resistance leads to a worse prognosis and other treatments such as DNA damaging drugs or radiation to eliminate these cells. Resveratrol (RSV) is a polyphenolic- compound found in plants such as grapes and hellebore and is known to evoke anti-cancer effects. While natural resveratrol exists as a mixture of both cis- and trans- isomers, so far, the isomer specific anti-cancer effects of RSV and their mechanisms of action of growth inhibitory effects are not well understood. Most recent studies have demonstrated that eukaryotic tyrosyl-tRNA synthetase (TyrRS)- an essential component of the protein synthesis machinery is a direct target of cis-RSV. While there are no apparent differences in the cellular levels of TyrRS in the WT T47D cells, treatment with cis-RSV resulted in a significant upregulation of TyrRS in the Tam resistant (TamR) T47D cells. Consistent with the inhibitory effect of cis-RSV on the L-tyrosine activation for protein synthesis by TyrRS, treatment with cis-RSV resulted in a greater growth inhibition in TamR T47D cells. Further, cellular signaling pathway analysis demonstrated that treatment with cis-RSV also resulted in a pronounced inhibitory effect on mammalian target of rapamycin complex 1 (mTORC1) signaling that drives protein synthesis in the TamR T47D cells. Therefore, cis-RSV-mediated inhibition of mTOR signaling and TyrRS function in translation would in part be responsible for the growth inhibitory effects of cis-RSV. However, unlike cis-RSV, trans-RSV evoked growth inhibitory effects in both WT and TamR T47D. Although trans-RSV downregulated TyrRS in WT T47D, it did not affect TyrRS levels in TamR T47D. Therefore, utilizing a combination of growth inhibition assays, immunofluorescent imaging and western blot analysis primarily within WT and TamR T47D cells, this study implies that the anti-cancer effect of cis-RSV correlates with the cellular level of TyrRS whereas the anti-cancer effects of trans-RSV is independent of cellular level of TyrRS.

Available for download on Monday, August 15, 2022