Osteolytic effects of tumoral estrogen signaling in an estrogen receptor-positive breast cancer bone metastasis model
Year: 2021
Type: article
Abstract: 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 2 )-dependent ER+ breast cancer BMET model.Methods: Female athymic Foxn1 nu 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 2dose 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 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.
Institution: University of Arizona
Language: English
Topic: Bone health and treatments
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W3148822709