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Abstract
Genistein, the major isoflavone in soybean, has been reported to exert anticancer effects on various types of cancer including ovarian cancer; however, its chemopreventive effects and mechanisms of action in ovarian cancer have not been fully elucidated in spontaneously developing ovarian cancer models. In this study, we demonstrated the preventive effects and mechanisms of genistein in the laying hen model that develops spontaneous ovarian cancer at high incidence rates. Laying hens were randomized to three groups: control (3.01 mg/hen, n = 100), low (52.48 mg/hen n = 100), and high genistein supplementation (106.26 mg/hen/day; per group). At the end of 78 weeks, hens were euthanized and ovarian tumors were collected and analyzed. We observed that genistein supplementation significantly reduced the ovarian tumor incidence (P = 0.002), as well as the number and size of the tumors (P = 0.0001). Molecular analysis of the ovarian tumors revealed that genistein downregulated serum malondialdehyde, a marker for oxidative stress and the expression of NFκB and Bcl-2, whereas it upregulated Nrf2, HO-1, and Bax expression at protein level in ovarian tissues. Moreover, genistein intake decreased the activity of mTOR pathway as evidenced by reduced phosphorylation of mTOR, p70S6K1, and 4E-BP1. Taken together, our findings strongly support the potential of genistein in the chemoprevention of ovarian cancer and highlight the effects of the genistein on the molecular pathways involved in ovarian tumorigenesis.
Highlights
Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related mortality among women in the United States
To investigate the effects of genistein supplementation on the development of spontaneous ovarian tumors, a total of 300 laying hens at age of 182 weeks were randomized to three groups (n 1⁄4 100 per group): (i) control (3.01 mg/day genistein), (ii) low-dose genistein (LG; 52.48 mg/hen/day), and (iii) high-dose genistein (HG; 106.26 mg/hen/day; Supplementary Fig. S1)
The incidence of ovarian cancer significantly decreased in both LG- and HG-treated hens (19% and 10%, respectively) compared with control group (P 1⁄4 0.002), indicating that genistein acts in a dose-dependent manner
Summary
Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related mortality among women in the United States. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/). New cases of ovarian cancer and 14,240 deaths (accounting for 5% of cancer-related deaths among women) are expected in the United States in 2016 [1]. The lack of reliable screening tests for detection of ovarian cancer at early stages, high rate of recurrence after surgery, and resistance to available chemotherapeutic drugs lead to poor prognosis and high mortality, with an overall 5-year survival rate of 46% [1, 6,7,8]. There is an urgent need for novel therapeutic agents that target specific molecular defects and have the potential to prevent ovarian cancer and improve outcomes for patients with ovarian cancer
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