Abstract LB127: An unconventional antiestrogen reveals the novel therapeutic target, DKK1, in aggressive ER+ breast cancer

Abstract Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Over 75% of breast cancer cases overexpress the hormone receptor estrogen receptor alpha (ERα), making it an attractive target for therapeutics. Although these therapies boast initial success, about 50% of women will experience disease recurrence in their lives. This disease returns aggressively, with many women having metastatic lesions with somatic mutations to ERα. One of the most clinically relevant mutation is a missense tyrosine to serine at position 537 of the receptor (Y537S). Developing treatments with higher efficacy that uniquely target pathways harnessed by Y537S ERα is urgently needed. To this end, our laboratory seeks to uncover hidden transcriptional programs specifically harnessed by Y537S ERα an unconventional antiestrogen termed T6I-29. We find that T6I-29 shows anti-tumoral activities in Y537S mutant xenograft murine models. Transcriptionally, T6I-29 uniquely downregulates DKK1, a secreted glycoprotein. The role of DKK1 is poorly understood in the context of ER+ breast cancer but has shown immunosuppressive and oncogenic properties in other cancer types. To first assess the relevance of DKK1 in ER+ breast cancer, we procured 108 ER+ breast cancer patient plasma samples and compared them to 100 matched healthy donors. Importantly, we find that DKK1 is significantly elevated in patient plasma. It has been previously reported in other cancer types that DKK1 specifically blunts the cytotoxicity of natural killer (NK) cells, an innate immune cell population critical for host defense. To explore the immunomodulatory effects of DKK1 in ERα+ breast cancers, we co-cultured NK cells with ERα+ breast cancer cells with and without the Y537S mutation and low and high levels of DKK1, respectively. We also cultured NK cells with recombinant DKK1. Importantly, we find that high levels of DKK1 and breast cancers with high DKK1 blunt the cytotoxicity of NK cells, which, when treated with T6I-29, are reinvigorated. Assessing other critical immune cell populations is important for further immunosuppressive characterization of DKK1 in ERα+ breast cancer. These novel findings potentiate DKK1 as a target in ERα+ breast cancers. Citation Format: Kristen Young, Govinda R. Hancock, Steven Kregel, Sean W. Fanning. An unconventional antiestrogen reveals the novel therapeutic target, DKK1, in aggressive ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB127.