Author ORCID Identifier

Defense Date


Document Type


Degree Name

Master of Science


Pharmacology & Toxicology

First Advisor

David Gewirtz


Breast cancer is the most commonly occurring malignancy in females, accounting for the second most common cause of cancer-related deaths. ER+ breast cancer constitutes approximately 70% of all breast cancer cases. The standard care of therapy comprises endocrine antagonists together with adjuvant therapy; however, the recovery from the therapy-suppressive state is associated with further drug resistance together with increasing tumor aggressiveness and with possible metastasis. Autophagy induction has been shown to be associated with various therapeutic modalities, with different functions, including cytotoxic, cytoprotective, cytostatic as well as non-protective forms. The triggering of autophagy may be responsible for resistance development and apoptosis suppression in the form known as cytoprotective autophagy, whereupon autophagy inhibition would represent a possible strategy to increase the effectiveness of various chemotherapeutic agents. Initially, we showed that Fulvestrant plus Palbociclib, one standard care of therapy, induces autophagy; therefore, we hypothesized that autophagy inhibition could increase the effectiveness of this combination. However, autophagy inhibition either genetically our pharmacologically resulted in only slight sensitization, suggesting that the autophagy role here is largely non-protective. Alternatively, we showed that Fulvestrant plus Palbociclib drives the ER+ cells into senescence, a state of reversible growth arrest, from which the cells begin to recover between days 12-18. Another strategy that being investigated to increase the effectiveness of endocrine therapies is by utilizing senescence targeting drugs including senomorphics, senostatics as well as senolytics. Furthermore, an association between senescence and epigenetic targets is demonstrable in that a member of the BET family, BRD4, has been shown to be overexpressed in breast cancer together with its downstream effector c-Myc, making it a possible therapeutic target. Therefore, we hypothesized that the BRD4 inhibitors, ARV-825 or ABBV-744, could increase the effectiveness of endocrine therapies, Tamoxifen and Fulvestrant plus Palbociclib. ARV-825 showed promising results together with Tamoxifen and Fulvestrant plus Palbociclib, with a potential senolytic activity against the senescent population induced by Fulvestrant plus Palbociclib. Moreover, ABBV-744 showed a p53-dependent growth inhibition when combined with Fulvestrant plus Palbociclib; however, ABBV-744 did not affect the proliferation or the viability of Tamoxifen-treated cells. Thses studies highlight the effectiveness of ARV-825 in vitro, and the need for testing the drug in resistant cell lines as well as in vivo using mice models.


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