Abstract Statement of Purpose: Breast cancer bone metastasis remains a major clinical challenge, with a five-year survival rate of only ∼22% following distant recurrence. Treatment is hindered by therapeutic resistance, frequent metastasis relapse, and the emergence of secondary metastases, all of which contribute to poor patient outcomes. Understanding the molecular mechanisms driving these processes is critical. ZMYND8, a chromatin reader, has emerged as a key player in cancer biology. It is involved in histone modification recognition, DNA repair, and can also promote angiogenesis under hypoxic conditions. Importantly, ZMYND8 has been identified as a prognostic marker in breast and liver cancers. Our preliminary data show that ZMYND8 is significantly upregulated in bone metastases compared to naïve tumor cells in an MCF7 estrogen receptor-positive (ER+) breast cancer model. This suggests that ZMYND8 may play an active role in metastatic progression.To elucidate its function, we are employing both in vitro and in vivo ER+ breast cancer models. This research will advance our understanding of ZMYND8 in metastasis and potentially uncover new therapeutic targets. Methods: We developed ZMYND8 knockdown in MCF-7 cell lines expressing firefly luciferase. Cell proliferation of knockdown vs control cells was studied with two methods: IVIS imaging of bioluminescence and BrdU assay. Cell migration was studied using a transwell system. The number of cells that migrated was stained with crystal violet and counted. Wound healing assay was performed by scratching cells in culture and measuring area of the scratch after 96h. Immunofluorescence staining was performed on patient samples with ZMYND8 antibody and Pan-Keratin antibody. Tumor vs stomal cells were separated based on Pan-Keratin expression and ZMYND8 expression. ZMYND8 expression was quantified by fluorescence intensity in primary breast tumor vs bone metastasis and in bone tumor vs stroma. DNA damage was quantified based on γH2AX staining. ZMYND8 knockdown and control MCF-7 cells were injected to the intra-iliac artery of nude mice and tumor growth was measured with IVIS. Results: In vitro studies demonstrated that ZMYND8 significantly enhances the metastatic potential of ER+ breast cancer cells. Specifically, knocking down ZMYND8 in MCF7 cells decreased migration, proliferation, and wound healing capacity compared to control cells. In Immunofluorescence analysis on patient bone metastasis samples, ZMYND8 is more highly expressed in bone metastasis than primary breast tumor, and it is also more highly expressed in the tumor cells compared to stromal cells in the bones. ZMYND8 also co-localized with yH2AX staining, and their expression shows a linear correlation, indicating ZMYND8 is highly expressed at DNA damage sites. In vivo study showed less growth of ZMYND8 knockdown cells in mouse compared to control cells at 35 days, suggesting ZMYND8’s role in tumor progression. Conclusion: Collectively, these results implicate ZMYND8 as a critical regulator of breast cancer bone metastatic progression and highlight its potential as a therapeutic target in ER+ breast cancer. Ongoing and future research includes in vivo studies to understand ZMYND8’s role in bone metastasis progression, mechanistic studies to investigate its molecular activities, and its therapeutic implications. Citation Format: T. Qin, I. Bado. Chromatin Reader ZMYND8 Promotes Breast Cancer Bone Metastasis abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-12-16.
Qin et al. (Tue,) studied this question.