Abstract 2594: Estrogen-regulated cytokine and growth factor secretion from breast cancers of women of diverse ancestry and effects on myelopoiesis

Abstract Breast cancer (BC) is the most common cancer among women in the U.S. It disproportionately affects African American (AA) women who have earlier disease onset, more aggressive subtypes, and lower survival rates compared to European American (EA) women. AA tumors show distinct gene variants linked to poor BC outcomes and immune signatures with differential expression of cytokines/chemokines potentially driving a more immunosuppressive tumor microenvironment (TME). Of note, cancer-related inflammation promotes aberrant myelopoiesis in bone marrow mediated distantly by tumor secretion of specific factors that stimulate accumulation of immunosuppressive myeloid cells. We have previously reported that estrogen signaling induces the expansion of myeloid derived suppressor cells (MDSCs), an action that can be blocked by selective estrogen receptor degraders (SERD), such as fulvestrant and our newly-designed oral SERD, JD128. To explore potential differences in cytokine/chemokine/growth factor secretion patterns in BC cells from EA and AA women, we used a Luminex multiplex assay to detect 38 cytokines/growth factors. Findings indicate different patterns of secretion occur, with AA cells showing significantly higher extracellular levels of CXCL9, MCP1, IL-8, PDGF-AB/BB, VEGF, TNF⍶ and G-CSF under basal conditions as compared to EA cells (P<0.05). Further, treatment with estradiol-17β stimulated secretion of TNFα, IL8, IL13, IL18, MCP1, G-CSF and PDGF-AA, an action that was significantly inhibited by use of SERDs fulvestrant or JD128 (P<0.05). TNF⍶ and G-CSF are known to promote myelopoiesis and a greater ratio of MDSC/CD8 T-cells, thereby potentially contributing to an immunosuppressive state in the TME. Further, estrogen stimulated proliferation of CD34+ bone marrow stem cells and MDSCs derived from normal female donors, an effect inhibited by fulvestrant and JD128 indicating that hematopoietic stem cells express estrogen receptors and respond to estrogen. Notably, using ELISA and qRT/PCR, SERDs fulvestrant and JD-128 decreased expression of transcript and protein levels of estrogen receptor alpha (P<0.05). Our preliminary data provides further evidence of a biologically distinct immunosuppressive profile that may drive more aggressive BC outcomes in AA women. Estrogen-mediated effects on hematopoietic cells may have implications for use of SERDs for estrogen receptor positive or negative BC. Funded by CIRM DISC2-14166, UCLA JCCC Breast Cancer Award, Tower Cancer Research Foundation, NIH/NCI U54 CA143930 CDU-UCLA JCCC Partnership, CBCRP B27IB3869, CDMRP DOD BCRP. Citation Format: Marisol Chavez, Mario Morales Martinez, Eduardo Mauricio Gonzalez, Gang Deng, Julia Aguade Gorgorio, Madhuri Wadehra, Nalo Hamilton, Michael E. Jung, Evelyn Jiagge, Sofia Merajver, Hannah Mikkola, Richard J. Pietras, Diana Marquez-Garban. Estrogen-regulated cytokine and growth factor secretion from breast cancers of women of diverse ancestry and effects on myelopoiesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2594.