Breast cancer is the major cause of
cancer death in women worldwide. The most common site of
metastasis is bone. Bone
metastases obstruct the normal bone remodeling process and aberrantly enhance osteoclast-mediated
bone resorption, which results in osteolytic lesions. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an endogenous
ligand of
peroxisome proliferator-activated receptor gamma (PPARγ) that has anti-inflammatory and antitumor activity at micromolar concentrations through PPARγ-dependent and/or PPARγ-independent pathways. We investigated the inhibitory activity of
15d-PGJ2 on the bone loss that is associated with
breast cancer bone
metastasis and
estrogen deficiency caused by
cancer treatment.
15d-PGJ2 dose-dependently inhibited viability, migration, invasion, and
parathyroid hormone-related protein (
PTHrP) production in MDA-MB-231
breast cancer cells.
15d-PGJ2 suppressed
receptor activator of nuclear factor kappa-B ligand (RANKL)
mRNA levels and normalized
osteoprotegerin (OPG)
mRNA levels in hFOB1.19 osteoblastic cells treated with culture medium from MDA-MB-231 cells or
PTHrP, which decreased the RANKL/OPG ratio.
15d-PGJ2 blocked RANKL-induced osteoclastogenesis and inhibited the formation of resorption pits by decreasing the activities of
cathepsin K and
matrix metalloproteinases, which are secreted by mature osteoclasts.
15d-PGJ2 exerted its effects on
breast cancer and bone cells via PPARγ-independent pathways. In Balb/c nu/nu mice that received an intracardiac injection of MDA-MB-231 cells, subcutaneously injected
15d-PGJ2 substantially decreased metastatic progression,
cancer cell-mediated bone destruction in femora, tibiae, and mandibles, and serum
PTHrP levels.
15d-PGJ2 prevented the destruction of femoral trabecular structures in
estrogen-deprived ICR mice as measured by bone morphometric parameters and serum biochemical data. Therefore,
15d-PGJ2 may be beneficial for the prevention and treatment of
breast cancer-associated
bone diseases.