Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

Breast cancer overall is the second most common cause of cancer related death in women, with one in eight women being diagnosed during their lifetime. Breast cancer itself is divided into subtypes based on the expression levels of the hormone receptors including the estrogen receptor (ER) and the progesterone receptor (PR), as well as expression of the growth factor receptor epidermal growth factor receptor 2 (HER2). ER+ breast cancer is the most common breast cancer diagnosis, and these tumors are defined as being initially dependent on activation of the receptor for growth. Based on this, targeted endocrine therapies (ETs) have been designed to inhibit the ER to block the growth of these tumor cells. Overall, ETs are highly effective as they are associated with better outcomes and lower rates of recurrence than non-targeted therapies. However, long term recurrence rates in these patients still remain high and are relatively unchanged during the 5 years a patient undergoes ET compared to the following 5 years of no treatment. This suggests that in a subset of patients that experience recurrence, ET alone may be insufficient to prevent cancer recurrence. Tumor initiating cells (TICs) are one cell type thought to contribute to recurrence in ER+ breast cancer. This is thought to be due to the persistence of these cells during ET, as they express relatively low levels of the ER and are hence intrinsically resistant to their anti-ER effects. Thus, although TICs make up a relatively small percentage of the tumor cell population, they remain within the tissue and overtime can recapitulate formation of a heterogeneous, aggressive tumor. TICs in ER+ breast cancer were shown to be dependent on NOTCH signaling, and it was illustrated that ET increases activation this pathway. Hence ET is thought to select for TICs by increasing NOTCH signaling. To prevent this, pharmaceuticals that inhibit NOTCH activation like γ-secretase inhibitors (GSIs) were developed for clinical use in combination with ETs. The hypothesis being ET will inhibit growth of the ER-dependent bulk tumor cells, and the GSI will inhibit TIC-survival. Preclinical results were promising, however the side effect profiles in patients made the use of GSIs in the clinic sub-optimal. Ultimately these findings indicated there was still a need for therapeutics that prevent TIC-survival in ER+ breast cancer. In a recent biomarker clinical trial, we identified a reported transcriptional repressor, DAXX, as a potential new target to prevent TIC-survival. Additional experiments indicated that DAXX was dependent on ER activation for its protein expression, thus under ET conditions, DAXX protein was depleted. Further, DAXX was shown to be required for ER restriction of TIC-survival and NOTCH signaling, and under ET conditions, overexpression of DAXX is sufficient to have the same effect. Together these findings suggested that DAXX was a bonafide repressor of TICs. Moreover, a therapeutic regimen that includes ET + a DAXX promoting agent may improve outcomes in patients with high risk of recurrence. We have illustrated that ET + partial agonists of the ER are sufficient to increase DAXX protein levels and decrease TIC-survival, without stimulating ER-dependent bulk tumor cell proliferation. Further, we have demonstrated both DAXX and the ER were required for these anti-TIC effects. Overall our results suggest that combination therapy of ET + a DAXX promoting agent represents a novel strategy to prevent TIC-survival, and ultimately improve outcomes in a subset of ER+ breast cancer patients.

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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