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

AIM

Estrogen receptor α-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 ERα signaling in driving ER+ BMET osteolysis was queried using an estrogen (E)-dependent ER+ breast cancer BMET model.

METHODS

Female athymic Foxn1 mice were inoculated with human ER+ MCF-7 breast cancer cells via the left cardiac ventricle post-E pellet placement, and age- and dose-dependent E effects on osteolytic ER+ BMET progression, as well as direct bone effects of E, were determined.

RESULTS

Osteolytic BMETs, which did not form in the absence of E supplementation, occurred with the same frequency in young (5-week-old) skeletally mature (16-week-old) E (0.72 mg)-treated mice, but were larger in young mice where anabolic bone effects of E were greater. However, in mice of a single age and across a range of E doses, anabolic E bone effects were constant, while osteolytic ER+ BMET lesion incidence and size increased in an E-dose-dependent fashion. Osteoclasts in ER+ tumor-bearing (but not tumor-naive) mice increased in an E-dose dependent fashion at the bone-tumor interface, while histologic tumor size and proliferation did not vary with E dose. E-inducible tumoral secretion of the osteolytic factor parathyroid hormone-related protein (PTHrP) was dose-dependent and mediated by ERα, with significantly greater levels of secretion from ER+ BMET-derived tumor cells.

CONCLUSION

These results suggest that tumoral ERα signaling may contribute to ER+ BMET-associated osteolysis, potentially explaining the greater predilection for ER+ tumors to form clinically-evident osteolytic BMETs.