Advanced hormone receptor-positive breast cancer frequently metastasizes to the bone marrow. Despite the introduction of endocrine therapy, over 50% of patients show evidence of tumour cells in the bone, and up to 30% eventually develop drug-resistant bone metastases. Understanding the role of estrogen in bone marrow (BM) homeostasis is crucial, as BM provides a supportive niche for disseminated tumour cells to survive and eventually form metastases. Notably, endocrine therapies modulate estrogen receptor (ER) signalling differently in various cell types. While Fulvestrant act as ER antagonist in breast cancer, Tamoxifen function as a partial agonist in certain BM immune cells, emphasizing the need to explore how these therapies alter the BM microenvironment and contribute to metastatic niche formation.
This project aims to elucidate how estrogen and endocrine therapies influence the cellular composition and functional dynamics of the BM niche, and how these changes affect metastatic cell colonization and adaptation. Using a cancer and treatment-naïve mouse model, we observed a significant increase in bone density, as measured by micro-computed tomography, following supplementation with human physiological concentrations of estrogen. Highly multiplexed flow cytometry analysis revealed that multiple hematopoietic populations—including stem cells, eosinophils, B cells, NK cells, and CD8+ T cells—express ER and respond to estrogen signaling, independent of changes to the bone’s structural properties. This highlights the importance of estrogen in modulating immune responses within the BM, potentially promoting or inhibiting early metastatic seeding.
In the 4T1.2 syngeneic mouse model of breast cancer, treatment with Fulvestrant—but not Tamoxifen— suppressed spontaneous bone metastasis. This was accompanied by an increase in immune cell numbers, particularly B lymphocytes, effector memory CD8+ T cells and eosinophils, which the latter is known to suppress breast tumor growth. Given that endocrine therapy remains the first-line therapy for breast cancer bone metastases, these findings suggest that different drugs may exert distinct mode-of-action in the bone marrow and additional investigations are needed to clarify their effectiveness in controlling bone metastasis.