Date of Award
Master of Science (MS)
In 2017, it is estimated that breast cancer will be the most prevalent newly diagnosed cancer in females, at 30% in the U.S. alone1. From the early 1990s to 2014 the death rate in females from breast cancer has dropped by 10% but still stands as the second highest cancer related death in females in the U.S.2. One of the biggest hurdles in breast cancer research is disease heterogeneity. New mechanisms of disease development and progression are encountered frequently. One mechanism studied in the past decades is epigenetics. It has been theorized that the cancer epigenome can maintain an abnormal state and possibly cooperate with genetic mutations3 and/or epigenetic modulators can be mutated which may become critical for cancer survival4. MLL1 (KMT2A), an epigenetic modulator that regulates gene expression by trimethylation of H3K4 near gene promoters, has recently been implicated in cancer. Data mining of publicly available primary patient databases revealed that high MLL1 expression is associated with decreased probability of recurrence-free survival in triple negative breast cancer (TNBC). In breast cancer cell lines that represent different breast cancer subtypes we tested the efficacy of pharmacological MLL1 inhibition and MLL1 knockdown. Our data suggests that MLL1 is crucial for anchorage independent growth of the MDA-MB-468 cell line and this is not dependent on high MLL1 expression. The use of an MLL1-specific inhibitor in combination with standard of care chemotherapeutic agents was shown to be more effective for all breast cancer cell lines tested; the drugs could be used at much lower doses when combined. Some of the many MLL1 specific gene targets (ABCG2, AMIGO2 and EMP1) were interrogated for changes in gene expression with MLL1 inhibition. To our surprise the observed changes varied between the cell lines suggesting that MLL1 inhibition differentially affects expression of specific genes in different cellular contexts. In conclusion, we demonstrate that MLL1 may be a viable target for breast cancer therapy in combination with standard of care agents. We also suggest that MLL1-dependent gene expression mechanisms could decrease drug resistance or impact cell survival.
Holmes, Austin Gable, "Potential Efficacy of Targeting MLL1 in Breast Cancer" (2017). Master's Theses. 3678.
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Copyright © 2017 Austin Gable Holmes