Osteolytic effects of tumoral estrogen signaling in an estrogen receptor-positive breast cancer bone metastasis model

Aim: Estrogen receptor a-positive (ER+) subtypes of breast cancer have the greatest predilection for forming osteolytic bone metastases (BMETs). Because tumor-derived factors mediate osteolysis, a possible role for tumoral ERa signaling in driving ER+ BMET osteolysis was queried using an estrogen (E 2)-dependent ER+ breast cancer BMET model. Methods: Female athymic Foxn1nu mice were inoculated with human ER+ MCF-7 breast cancer cells via the left cardiac ventricle post-E-2 pellet placement, and age- and dose-dependent E-2 effects on osteolytic ER+ BMET progression, as well as direct bone effects of E-2, were determined. Results: Osteolytic BMETs, which did not form in the absence of E-2 supplementation, occurred with the same frequency in young (5-week-old) vs. skeletally mature (16-week-old) E-2 (0.72 mg)-treated mice, but were larger in young mice where anabolic bone effects of E-2 were greater. However, in mice of a single age and across a range of E-2 doses, anabolic E-2 bone effects were constant, while osteolytic ER+ BMET lesion incidence and size increased in an E-2 dose-dependent fashion. Osteoclasts in ER+ tumor-bearing (but not tumor-naive) mice increased in an E-2 dose dependent fashion at the bone-tumor interface, while histologic tumor size and proliferation did not vary with E-2 dose. E-2-inducible tumoral secretion of the osteolytic factor parathyroid hormone-related protein (PTHrP) was dose-dependent and mediated by ERa, with significantly greater levels of secretion from ER+ BMET-derived tumor cells. Conclusion: These results suggest that tumoral ER alpha signaling may contribute to ER+ BMET-associated osteolysis, potentially explaining the greater predilection for ER+ tumors to form clinically-evident osteolytic BMETs.