Recent clinical and epidemiological evidence shows that
hormone replacement therapy (HRT) containing both
estrogen and
progestin increases the risk of primary and metastatic
breast cancer in post-menopausal women while HRT containing only
estrogen does not. We and others previously showed that
progestins promote the growth of human
breast cancer cells in vitro and in vivo. In this study, we sought to determine whether
apigenin, a low molecular weight anti-carcinogenic
flavonoid, inhibits the growth of aggressive Her2/neu-positive BT-474 xenograft
tumors in nude mice exposed to
medroxyprogesterone acetate (MPA), the most commonly used
progestin in the USA. Our data clearly show that
apigenin (50 mg/kg) inhibits progression and development of these xenograft
tumors by inducing apoptosis, inhibiting cell proliferation, and reducing expression of Her2/neu. Moreover,
apigenin reduced levels of
vascular endothelial growth factor (
VEGF) without altering blood vessel density, indicating that continued expression of
VEGF may be required to promote
tumor cell survival and maintain blood flow. While previous studies showed that MPA induces
receptor activator of nuclear factor kappa-B ligand (RANKL) expression in rodent mammary gland, MPA reduced levels of RANKL in human
tumor xenografts. RANKL levels remained suppressed in the presence of
apigenin. Exposure of BT-474 cells to MPA in vitro also resulted in lower levels of RANKL; an effect that was independent of
progesterone receptors since it occurred both in the presence and absence of the antiprogestin
RU-486. In contrast to our in vivo observations,
apigenin protected against MPA-dependent RANKL loss in vitro, suggesting that MPA and
apigenin modulate RANKL levels differently in
breast cancer cells in vivo and in vitro. These preclinical findings suggest that
apigenin has potential as an agent for the treatment of
progestin-dependent
breast disease.