Combined hormone therapy (HT) containing estrogen and progestin (medroxyprogesterone acetate [MPA]) leads to increased risk of breast cancer in postmenopausal women, compared with HT regimens containing estrogen alone or placebo. We previously reported that in animal models, progestins can accelerate the development of mammary tumors by increasing vascular endothelial growth factor (VEGF) levels. We furthermore showed that curcumin, an Indian spice derived from the turmeric root, specifically inhibits MPA-induced VEGF secretion from breast cancer cells in vitro. In the present study, we investigated whether curcumin inhibits 7,12-dimethylbenz[a]anthracene (DMBA)-induced, MPA-accelerated tumors in Sprague-Dawley rats.
On day 0, virgin female Sprague-Dawley rats (age, 55 d) were given DMBA (20 mg/rat). Sixty-day timed-release pellets containing 25 mg MPA were implanted into the rats on day 30. Curcumin was administered daily at a rate of 200 mg kg−1 day−1 from days 26 to 50, and animals were killed on day 52 (n = 15-19 per group).
Treatment with curcumin delayed the first appearance of MPA-accelerated tumors by 7 days, decreased tumor incidence by the end of the experiment, and reduced tumor multiplicity in DMBA-induced MPA-accelerated tumors. Curcumin also prevented many of the gross histological changes seen in the MPA-treated mammary gland. Immunohistochemical analyses of mammary tumors showed that curcumin decreased MPA-induced VEGF induction in hyperplastic lesions, although it did not affect the levels of estrogen and progesterone receptors.
We suggest that curcumin be tested as a dietary chemopreventive agent in women already exposed to MPA, in an effort to decrease or delay the risk of breast cancer associated with combined HT.
This article provides evidence that the dietary component of curcumin effectively delays medroxyprogesterone acetate-accelerated mammary tumor formation and tumor multiplicity in Sprague-Dawley rats. Curcumin also prevents morphological changes associated with cancer in the mammary gland of medroxyprogesterone acetate-treated animals. These observations suggest that curcumin has the potential to delay or inhibit progestin-dependent breast cancer in postmenopausal women.
From the 1Department of Biomedical Sciences; 2Dalton Cardiovascular Research Center; 3Department of Pathology; and 4Agriculture Experiment Station, University of Missouri, Columbia, MO.
Received February 24, 2009; revised and accepted April 27, 2009.
Funding/support: This research was supported by National Institutes of Health Grant CA-86916 and in part by R56CA-86916 from the National Cancer Institute; PDF0600723 from the Susan Komen for Cure grants; Funds from Research Diagnostic Lab and a COR grant, both from the University of Missouri College of Veterinary Medicine; a National Institutes of Health-funded Minority Biomedical Research Training Initiative grant from the Department of Veterinary Pathobiology; and a Phi Zeta, Pi Chapter grant.
Financial disclosure/conflicts of interest: S.M.H. is the Zalk Missouri Professor of Tumor Angiogenesis.
Address correspondence to: Salman M. Hyder, PhD, Dalton Cardiovascular Research Center, 134 Research Park Drive, Columbia, MO 65211. E-mail: email@example.com