(P 136) ESTROGEN HAS A PROTECTIVE EFFECT ON CHONDROSARCOMA GROWTH IN VITRO AND IN VIVO

Objective: Chondrosarcoma, the most common primary bone malignancy in adults, accounts for approximately 25% of primary bone cancers. Surgical resection of localised tumours with adequate margins remains the primary treatment option, underscoring the need for novel therapeutic strategies. Chondrosarcoma affects men more than women (ratio1.5:1) and recent clinical data suggests that women have improved survival compared to men of comparable age. This effect diminishes after the age associated with menopause suggesting that estrogen may have a protective effect in chondrosarcoma. Here, we present novel data that shows that estrogen is indeed protective in chondrosarcoma and that this effect is largely mediated via the G-protein coupled estrogen receptor (GPER).

Methods: We validated the expression of all three estrogen receptors: ERα, ERβ, and GPER in both male (JJ012) and female (SW1353) chondrosarcoma cell lines via qPCR and western blotting. To understand which receptors predominantly mediate the protective effect of estrogen, we used selective ligands for each ER receptor subtype, and measured dose-dependent changes in cell proliferation. For the in vivo study, 7-week-old female NOD-scid gamma mice were subjected to ovariectomy (OVX), to mimic post-menopausal status, or sham-operated. One-week post-surgeries, mice were injected with 2.5e5 luciferase-expressing SW1353 cells subcutaneously and tumour burden monitored via bioluminescence imaging.

Results: GPER-selective ligand G1 inhibited cell proliferation of JJ012 (IC50 6.65e-7M) and SW1353 (IC50 3.54e-7M) cells over 72 hours compared to vehicle control. In contrast, propylpyrazoletriol (PPT; ERα-selective) and diarylpropionitrile (DPN; ERβ-selective) had minimal effects. For the in vivo study, at day 31, higher tumour burden was observed in the OVX mice compared to the sham controls (1.53e6 vs 6.76e5; P< 0.0001). Further studies are required to validate if these effects are also mediated predominantly via GPER.

Conclusion: These preliminary data indicate that estrogen plays a protective role in the progression of chondrosarcoma and are consistent with the clinical findings, and that selectively targeting GPER may have therapeutic potential in chondrosarcoma.