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    Research Grants Awarded

    Vitamin D Actions For The Prevention And Treatment Of Breast Cancer

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    RATIONALE. Our grant proposes to study the use of dietary vitamin D3 for the treatment of breast cancer (BCa). Dietary vitamin D3 is a prohormone that is easily converted by the liver to 25-hydroxyvitamin D3 [25(OH)D3], the circulating prohormone, which is then converted in the kidney to the active hormone calcitriol. We now know that normal breast and BCa cells can locally synthesize the active hormone calcitriol since they expresses 1-alpha-hydroxylase, the enzyme that converts circulating 25(OH)D3 to calcitriol. The presence of 1-alpha-hydroxylase in the BCa cells provides the rationale for using vitamin D3 as an anti-cancer agent in BCa. Thus in vivo therapy with dietary vitamin D3 subsequently leads to the local production of calcitriol within the breast. If the dose is adequate, dietary vitamin D3 will mediate all the actions of calcitriol in BCa cells. In our in vitro studies we will use 25(OH)D3, the prohormone, which will be converted locally in the BCa cells to calcitriol. Calcitriol has multiple well-documented anti-cancer actions to inhibit proliferation, stimulate apoptosis, promote differentiation, and inhibit angiogenesis and metastasis in both BCa cells and BCa animal models. In addition, three recent finding in BCa cells made in our lab indicate that locally synthesized calcitriol would be uniquely active in estrogen-dependent BCa: (1) Calcitriol inhibits the expression of the enzyme aromatase, which catalyzes estrogen synthesis. Thus calcitriol inhibits local estrogen synthesis and reduces the most important source of estrogen in the postmenopausal breast leading to the suppression of BCa growth. (2) Calcitriol inhibits the synthesis and actions of prostaglandins (PGs), which are major stimulators of aromatase transcription in BCa cells. Therefore PG inhibition by calcitriol indirectly reduces estrogen synthesis. (3) Calcitriol down-regulates the expression of estrogen receptor alpha (ER). Thus calcitriol decreases both the synthesis of estrogens and the receptor that mediates estrogen actions and thereby reduces estrogen stimulation to cause the proliferation and progression of ER(+) BCa. HYPOTHESIS AND EXPECTED RESULTS. Hypothesis #1: Since 1-alpha-hydroxylase is expressed in BCa cells, we hypothesize that dietary vitamin D3 will exert beneficial effects similar to calcitriol to decrease aromatase and ER expression by virtue of its conversion to 25(OH)D3 (in the liver) and subsequently to calcitriol within the BCa cells. Hypothesis #2: Vitamin D3 will inhibit estrogen signaling by down-regulating aromatase and ER leading to a significant inhibition of BCa cell growth. Hypothesis #3: Therapy with a combination of dietary vitamin D3 and an aromatase inhibitor (AI) will exhibit additive or synergistic effects to inhibit BCa growth and demonstrate enhanced anti-cancer activity. RESEARCH AIMS AND DESIGN. Aim I investigates vitamin D3 regulation of estrogen synthesis and ER expression in BCa cells comparing its activity to that of calcitriol. Sub Aim 1 studies the tissue-specific regulation of aromatase. Sub Aim 2 examines the regulation of ER expression, estrogenic bio-responses and inhibition of BCa cell growth by vitamin D3 and AIs and determines whether the combination of vitamin D3 and an AI exhibits enhanced potency. Sub Aim 3 explores the contribution of aromatase suppression and ER down-regulation to the anti-proliferative activity of vitamin D3 in BCa cells. Aim II assesses the in vivo efficacy of dietary vitamin D3, AIs and their combination in nude mice bearing human BCa xenografts. We will compare the effects of vitamin D3 and calcitriol to suppress estrogen signaling and tumor growth. PROJECT RELEVANCE TO REDUCING BCa INCIDENCE AND MORTALITY. Our research will significantly add to the therapeutic approaches available to treat BCa. Calcitriol exerts beneficial effects in BCa by multiple mechanisms including the inhibition of estrogen signaling. The results of the ASCENT clinical trial in men with advanced androgen-independent prostate cancer showed that when combined with the chemotherapy drug taxotere, high-dose calcitriol caused a major improvement (~50%) in overall survival and time to progression and decreased the serious taxotere side-effects. This trial provided ?proof of principle? that calcitriol can enhance the efficacy of active drugs and improve survival in cancer patients. We propose that dietary vitamin D3 will exhibit anti-BCa effects similar to calcitriol as it can be converted to calcitriol locally within the BCa cells. We propose that dietary vitamin D3 when used in combination with an AI will improve efficacy, reduce side-effects, increase the therapeutic window for both drugs and delay or prevent the development of AI resistance thereby preserving long-term remissions in patients. The advantages of dietary vitamin D3 over calcitriol include its acceptance as a natural nutritional factor, its economy, availability and safety, its extremely wide therapeutic window and the reduced likelihood to cause hypercalciuria or hypercalcemia. Our goal is to obtain the necessary preclinical data to rapidly advance dietary vitamin D3 plus AI combination therapy to clinical trials in ER(+) BCa patients.

    Lay Abstract:
    STUDY HYPOTHESIS. New safe and effective therapies are needed to treat breast cancer (BCa). Our hypothesis is that dietary vitamin D3 is one such new and safe nutritional agent that warrants study to define its efficacy and potency and to determine the best way to utilize it therapeutically. Vitamin D3 is not actually a vitamin but is a prohormone, which is converted in the body to calcitriol, a potent steroid hormone that exhibits many well-documented anti-cancer actions. Calcitriol exhibits anti-cancer actions in many cancers including BCa. These inhibitory actions in BCa include: inhibition of cell growth, reduction of angiogenesis, lessening of cancer progression and metastasis and stimulation of cellular differentiation. Dietary vitamin D3 is easily converted in the liver to 25-hydroxyvitamin D3 (the circulating prohormone), which is then converted in the kidneys to calcitriol by the enzyme 1-alpha-hydroxylase. Recent studies show that 1-alpha-hydroxylase is present within the normal breast and BCa cells. Thus by virtue of this enzyme in the breast and BCa cells, there is local conversion of circulating 25(OH)D3 to calcitriol within the BCa cells rendering dietary vitamin D3 the ability to exhibit all the beneficial effects of calcitriol. We have recently found three additional new calcitriol actions in BCa cells that indicate that vitamin D3, as the prohormone to calcitriol, would also exert. (1) Calcitriol decreases the levels of the enzyme aromatase. This action to inhibit the enzyme that catalyzes estrogen synthesis reduces the most important source of estrogen that is the proliferative stimulus in the postmenopausal breast or for BCa to grow. (2) Calcitriol inhibits the synthesis and actions of prostaglandins (PGs), the major stimulator of aromatase expression in BCa, thus indirectly inhibiting local estrogen synthesis in the breast. (3) Calcitriol reduces the levels of the estrogen receptor alpha (ER), the receptor that is essential to carry out estrogen actions. Thus calcitriol inhibits both the synthesis of estrogenic hormones and the ER that mediates estrogen action and thereby attenuates estrogen stimulation of the proliferation and progression of ER(+) BCa. Since vitamin D3 can be converted into calcitriol within the breast, one goal of the grant is to determine whether dietary vitamin D3 given in adequate amounts can also accomplish these same anti-cancer actions as calcitriol. Our findings have led us to propose three hypotheses to be tested in this grant. Hypothesis #1: Dietary vitamin D3 will exert beneficial effects similar to calcitriol to decrease aromatase and ER expression by virtue of its conversion to calcitriol within the breast. Hypothesis #2: Vitamin D3 will inhibit estrogen signaling, by decreasing both estrogen synthesis and ER levels leading to a significant inhibition of BCa cell growth. Hypothesis #3: Therapy with a combination of dietary vitamin D3 and an aromatase inhibitor (AI) will exhibit additive or synergistic effects to inhibit BCa growth and demonstrate enhanced anti-cancer activity compared to the individual agents. HOW OUR HYPOTHESIS WILL BE TESTED. Aim I will investigate vitamin D3 regulation of aromatase and ER in cultured BCa cells comparing its activity to calcitriol. We will study the effect of vitamin D3-AI combination to inhibit estrogenic bio-responses and block BCa cell growth and evaluate whether the combination improves the therapeutic efficacy and potency of the individual drugs. Aim II will assess the potency of dietary vitamin D3, AIs and their combination in a nude mouse model bearing human BCa xenografts. We will compare the effects of vitamin D3 and calcitriol to suppress estrogen signaling and tumor growth. HOW THE PROJECT ADVANCES OUR UNDERSTANDING OF BCa AND TO REDUCES BCa INCIDENCE AND MORTALITY. Our research will significantly add to the therapeutic approaches available to treat BCa. Calcitriol exerts beneficial effects in BCa by multiple mechanisms including the inhibition of estrogen signaling. We propose that dietary vitamin D3 will exhibit similar anti-BCa effects as it can be converted to calcitriol locally within the BCa cells. Further we propose that dietary vitamin D3 when used in combination with an AI will improve efficacy and reduce the AI side-effects of osteoporosis. The advantages of dietary vitamin D3 over calcitriol include its acceptance as a nutritional factor, its economy, availability and safety, its extremely wide therapeutic window and reduced likelihood to cause elevated levels of calcium (the only side-effect of calcitriol). THE IMPORTANCE OF THE RESEARCH TO PATIENTS WITH BCA. Currently AIs are used very effectively in post-menopausal BCa. However, it is predicted that long-term endocrine therapy with AIs will eventually lead to AI resistance in patients. We propose that the combination of vitamin D3 with an AI will be more potent either drug alone, will increase the therapeutic window for both drugs allowing lower, safer doses to be used and will delay or prevent the development of AI resistance thereby preserving long-term remissions in patients. Our goal is to obtain the necessary preclinical data to rapidly advance dietary vitamin D3-AI combination therapy to clinical trials in ER(+) BCa patients. In addition, our study will highlight the importance of dietary vitamin D3 for chemoprotection and treatment of BCa. We anticipate that our findings will make both physicians and patients aware of the importance of vitamin D status and the need for the evaluation and correction of vitamin D deficiency in BCa patients.