Date of Award
Master of Science (MS)
Breast cancer is the leading cause of cancer-related death in women globally, and one in eight women will be diagnosed with breast cancer at some point in her life. Alcohol consumption has been linked to increase breast cancer risk and increased risk of tumor recurrence. Understanding the molecular mechanisms of modifiable lifestyle factors such as alcohol consumption will help to lower these risks and design more effective therapeutic approaches. Estrogen Receptor positive (ER+) breast cancer comprises approximately 70% of all breast cancers, and these tumors are effectively targeted by endocrine therapy in the form of estrogen deprivation with aromatase inhibitors, a selective estrogen receptor modifier (tamoxifen), or a selective estrogen receptor degrader (fulvestrant). However, resistance to endocrine therapy poses a major threat to women with ER+ breast cancer. One proposed mechanism for drug resistance and tumor recurrence is explained by the cancer stem cell hypothesis, which states that tumors are composed of a heterogenous cell population that consists of differentiated and stem- like cells, coined cancer stem cells (CSCs). CSCs are able to evade endocrine therapy and remain dormant until later reactivated by the microenvironment, in which they then re-bulk a tumor, usually at the metastatic site. The effects of alcohol on ER+ breast CSCs have yet to be elucidated. The CSC population is known to be maintained by a variety of signaling pathways. Estrogen signaling is thought to maintain a differentiated state and suppress pluripotent populations, whereas Notch signaling is a known promoter of CSC populations and a necessary component of their survival. Thus, we propose the central hypothesis that alcohol promotes ER+ breast cancer stem cells through the activation of Notch signaling.
Preliminary data show that alcohol enhances ER+ breast CSC survival regardless of the presence of estrogen. Results show that Notch target genes HES1, SOX2, and others are induced upon exposure to 40mM ethanol in naïve ER+ breast cancer cells. On the contrary, exposure to ethanol resulted in attenuated induction of classic ER targets PS2 and PGR in response to treatment with 5nM estradiol. Additionally, inhibition of Notch signaling by a gamma-secretase inhibitor had no effect on the ability of ethanol to enhance breast CSC survival when estrogen was present, however under estrogen deprivation conditions Notch inhibition prevented breast CSC survival in the presence of ethanol. Lastly, investigation into the effects of alcohol on an endocrine therapy resistant cell line show a positive trend in breast CSC survival and induced Notch activation.
Taken together, these results indicate that alcohol mediates breast CSC survival partly through Notch activity under estrogen deprived conditions. However, Notch signaling may not be necessary for alcohol’s effect on the CSC population when estrogen is present based on our findings using a GSI in breast CSCs. Further studies are necessary to investigate the exact mechanism of alcohol on estrogen signaling and determine if the Notch activation seen when alcohol is present is due to direct activation of the pathway or through inhibition of its negative regulator, ER.
Below, Mckenna, "Characterization of Alcohol-Mediated Promotion of Breast Cancer Stem Cells" (2021). Master's Theses. 4379.
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