Aim:Estrogen receptorα-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...Aim:Estrogen receptorα-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 ERαsignaling in driving ER+BMET osteolysis was queried using an estrogen(E2)-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-E2 pellet placement,and age-and dose-dependent E2 effects on osteolytic ER+BMET progression,as well as direct bone effects of E2,were determined.Results:Osteolytic BMETs,which did not form in the absence of E2 supplementation,occurred with the same frequency in young(5-week-old)vs.skeletally mature(16-week-old)E2(0.72 mg)-treated mice,but were larger in young mice where anabolic bone effects of E2 were greater.However,in mice of a single age and across a range of E2 doses,anabolic E2 bone effects were constant,while osteolytic ER+BMET lesion incidence and size increased in an E2 dose-dependent fashion.Osteoclasts in ER+tumor-bearing(but not tumor-naive)mice increased in an E2-dose dependent fashion at the bone-tumor interface,while histologic tumor size and proliferation did not vary with E2 dose.E2-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 ERαsignaling may contribute to ER+BMET-associated osteolysis,potentially explaining the greater predilection for ER+tumors to form clinically-evident osteolytic BMETs.展开更多
基金supported by the National Cancer Institute(NCI)of the National Institutes of Health(NIH)(R03CA181893 and R01CA174926 to JLF,T32CA00923,P30CA023074)METAvivor(Translational Research Award,JLF)+1 种基金the Phoenix Chapter of ARCS Foundation(JNC)and the Louise Foucar Marshall Foundation Dissertation Fellowship(JNC).
文摘Aim:Estrogen receptorα-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 ERαsignaling in driving ER+BMET osteolysis was queried using an estrogen(E2)-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-E2 pellet placement,and age-and dose-dependent E2 effects on osteolytic ER+BMET progression,as well as direct bone effects of E2,were determined.Results:Osteolytic BMETs,which did not form in the absence of E2 supplementation,occurred with the same frequency in young(5-week-old)vs.skeletally mature(16-week-old)E2(0.72 mg)-treated mice,but were larger in young mice where anabolic bone effects of E2 were greater.However,in mice of a single age and across a range of E2 doses,anabolic E2 bone effects were constant,while osteolytic ER+BMET lesion incidence and size increased in an E2 dose-dependent fashion.Osteoclasts in ER+tumor-bearing(but not tumor-naive)mice increased in an E2-dose dependent fashion at the bone-tumor interface,while histologic tumor size and proliferation did not vary with E2 dose.E2-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 ERαsignaling may contribute to ER+BMET-associated osteolysis,potentially explaining the greater predilection for ER+tumors to form clinically-evident osteolytic BMETs.
