Date of Award

2026

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Science

First Advisor

Sean Fanning

Abstract

Over 70 percent of breast cancers are estrogen receptor-positive (ERα+), meaning that the hormone estrogen drives tumor growth. Although first-line targeted therapies that directly block ERα from hormone-dependent pathologies are initially effective, almost half of patients ultimately progress. These patients show high mutational rates to the ESR1 gene that encodes for ERα. A hotspot missense tyrosine to serine mutation at position 537 (Y537S) initiates hormone-independent, allele-specific transcriptional programs that increase metastasis. While next-generation ERα-targeted therapies show promise, benefits are often limited compared to standard-of-care. Understanding the mechanisms of action used by the Y537S ESR1 breast cancer cells to evade therapeutic efficacy is important in discovering novel treatment strategies. Recently, we developed a unique selective estrogen receptor modulator (SERM, a class of hormone therapy) to specifically target the Y537S ERα. This SERM, T6I-29, shows effective anti-tumoral activities in models of Y537S ESR1 breast cancer. To determine its mechanism of action, we performed transcriptomic analysis in these cells compared to treatments with clinically relevant drugs. Surprisingly, while these drugs showed highly similar transcriptome-wide effects, our drug significantly downregulated dickkopf-1 (DKK1), a secreted glycoprotein that is oncogenic in several cancers by inducing Natural Killer (NK) cellular dormancy. However, the role of DKK1 is understudied in ER+ breast cancer. Encouragingly, there is a DKK1 monoclonal antibody, DKN-01, that is in clinical trials for other cancer types and has shown promise when combined with standard-of-care treatments. In ERα+ breast cancer, we find that circulating DKK1 levels are significantly increased in patient plasma compared to healthy donor counterparts. Furthermore, we find a hormone-responsive secretion of DKK1 in WT and Y537S ESR1 breast cancer cells. However, this hormone-responsive secretion of DKK1 is dampened in cells that have high expression of the progesterone receptor (PR). Preliminary data with NK cells show endocrine therapies have differential effects on breast cancer killing ability when DKK1 levels are elevated. This work reveals the potential implication of DKK1 ER+ breast cancer as a therapeutic vulnerability in aggressive ER+ breast cancers.

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