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    Research Grants Awarded

    Prostaglandin Inhibition To Prevent Breast Cancer

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    The prevention of cancer requires the use of therapy which is efficacious with minimal toxicity. The only FDA approved medications to prevent breast cancer, tamoxifen and raloxifene, are associated with increased risk of blood clots and pulmonary emboli. Therapy using two agents with synergistic effects, maximizing the overall chemopreventive effect while minimizing the toxicity of each agent, is highly desirable. There is growing interest among women in bioactive dietary components as part of a healthy lifestyle. Vitamin D decreases breast cancer risk by controlling cell growth, and doses up to 2000 IU/day can be taken long term without toxicity. The anti-inflammatory agent celecoxib has been shown to decrease breast cancer risk. Both vitamin D and celecoxib inhibit prostaglandin (PG)E2. Vitamin D inhibits PGE2 by transcriptionally regulating cyclooxygenase (COX)-2 and 15-prostaglandin dehydrogenase (15-PGDH), enzymes involved in the synthesis and metabolism of PGE2. Celecoxib binds directly to COX-2 to inhibit PGE2 synthesis. CYP24 initiates the degradation of 1,25(OH)D2, the active form of vitamin D, and assessing its expression may predict the efficacy of vitamin D in breast cancer prevention. Vitamin D and celecoxib synergistically inhibit prostate cancer proliferation. Thus, there is potential for a synergistic effect of vitamin D with celecoxib in the breast, with vitamin D decreasing PGE2 by transcriptional regulation of enzymes, and celecoxib inhibiting PGE2 through a separate mechanism, leading to decreased cell growth. Our hypothesis is that vitamin D and celecoxib act synergistically to decrease breast cancer risk through their action on prostaglandin synthesis and metabolism, leading to decreased cell proliferation. In women at increased breast cancer risk, we will determine the effect of vitamin D, with or without celecoxib, on 1) prostaglandin synthesis and metabolism, through the measurement of PGE2, COX-2 and 15-PGDH in the breast, 2) vitD metabolism, through the measurement of CYP24 in the breast, and 3) circulating levels of 25(OH)D, 1,25(OH)D2 and celecoxib, and breast specific levels of 25(OH)D and celecoxib, and assess if the levels of these compounds correlate with response to markers which influence PG synthesis and metabolism. Participants will be randomized to receive one of three treatments: placebo, vitamin D, or vitamin D plus celecoxib. Intraductal samples from the breast and blood collected at baseline and after one and three menstrual cycles (premenopausal subjects) or one and three months (postmenopausal subjects) will be analyzed. This study is an essential step in humans to determine if two agents can be used together to maximize breast chemopreventive efficacy, while minimizing potential side effects. If proven effective, a multicenter study will be conducted, with the hope of using these agents to reduce breast cancer incidence within the next decade.

    Lay Abstract:
    The prevention of cancer requires the use of therapy which is efficacious with minimal toxicity. The only FDA approved medications to prevent breast cancer, tamoxifen and raloxifene, are associated with an increased risk of blood clots and pulmonary emboli. There is substantial evidence that vitamin D decreases breast cancer risk by controlling cell growth, and that doses up to 2000 IU/day can be taken long term without toxicity. The anti-inflammatory agent celecoxib has been shown to inhibit breast cancer growth in animal models and decrease breast cancer risk in epidemiologic studies in humans. We have found that in high risk women and in women with breast cancer, celecoxib 1) is delivered to the breast, 2) decreases the cancer promoting molecule prostaglandin (PG)E2, and 3) levels correlate with the decrease in PGE2 in the breast. Both vitamin D and celecoxib inhibit prostaglandin PGE2, but in different ways. Vitamin D inhibits PGE2 by regulating the production of cyclooxygenase (COX)-2, an enzyme involved in the synthesis of PGE2, and 15-prostaglandin dehydrogenase (15-PGDH), an enzyme which regulates the rate of metabolism (breakdown) of PGE2. Celecoxib binds directly to COX-2 to inhibit PGE2 synthesis. CYP24 initiates the degradation of 1,25(OH)D2, the active form of vitamin D, and therefore assessing its expression may provide clues to the potential efficacy of vitamin D in breast cancer prevention. Vitamin D and celecoxib have been shown to work in synergy to inhibit prostate cancer proliferation. Thus, there is potential for a synergistic effect of vitamin D with celecoxib in the breast, with vitamin D decreasing PGE2 by the regulation of enzymes which control PGE2 production and metabolism, and celecoxib inhibiting PGE2 through a separate mechanism. Our hypothesis is that vitamin D and celecoxib act synergistically to decrease breast cancer risk through their action on prostaglandin synthesis and metabolism, leading to decreased cell proliferation. In women at increased breast cancer risk, we will determine the effect of vitamin D, with or without celecoxib, on 1) PG synthesis and metabolism, through the measurement of PGE2, COX-2 and 15-PGDH in the breast, 2) vitD metabolism, through the measurement of CYP24 in the breast, and 3) circulating levels of 25(OH)D, 1,25(OH)D2, and celecoxib, and breast specific levels of 25(OH)D and celecoxib, and assess if the levels of these compounds correlate with response to markers which influence PG synthesis and metabolism. The strength of our approach is that it provides organ specific information using cells shed and proteins released from the breast ductal lining, the cells that give rise to 99% of breast cancers. This study is an essential step in humans to determine if two agents can be used together to maximize breast chemopreventive efficacy, while minimizing potential side effects. If the agents are found effective and synergistic, we will immediately propose a long term multicenter study using vitamin D along with a lower celecoxib dose of 200 mg daily, based on an exciting epidemiologic study in which women who took celecoxib 200 mg daily for at least two years demonstrated an 83% lower risk of breast cancer than those who did not.