The Development of Vitamin D as a Therapy for Breast Cancer

描述(由申请人提供)： 骨化三醇是维生素D3的激素活性形式，具有众所周知的抗癌活性。我们最近发现了四种新的骨化三醇抑制乳腺癌(BCA)生长的作用途径。(1)骨化三醇直接抑制BCA细胞和脂肪组织中芳香化酶的表达，从而减少局部雌激素的合成和对雌激素受体(ER)阳性的BCA细胞的主要生长刺激。重要的是，骨化三醇表现出对芳香化酶的组织特异性调节，导致BCA和脂肪组织的下调，以及骨骼的上调。后一种作用将保护骨骼免受骨质疏松的副作用，这是芳香酶抑制剂(AI)治疗患者中常见的因雌激素缺乏而引起的副作用。(2)骨化三醇通过抑制COX-2表达等多种作用，抑制BCA生长的主要刺激因子前列腺素(PG)的合成。(3)PGs是BCA芳香酶转录的有效诱导剂，骨化三醇对PGs的抑制也间接降低了芳香酶的表达。(4)骨化三醇直接下调ER1的表达。因此，骨化三醇通过多种途径降低配体(雌激素)和受体(ER)的水平，从而抑制BCA的生长。我们推测骨化三醇和AI联合治疗将提高AI的疗效、效力和安全性，降低骨质疏松的风险，延缓AI抵抗的发展。目的：我们将研究骨化三醇的这四条作用途径，并评价骨化三醇与人工血管紧张素转换酶抑制剂联合应用的有效性。这些研究将迅速为骨化三醇-AI联合治疗BCA患者的临床试验铺平道路。目的：研究骨化三醇对BCA、脂肪、卵巢和骨细胞芳香酶和PG途径基因的调节以及骨化三醇联合AI对BCA细胞生长的抑制作用。目的研究芳香酶的差异性调控机制。目的III确定骨化三醇下调ER1的机制。Aim IV的活体研究评估了骨化三醇、AIS及其组合在异种移植小鼠模型中对肿瘤生长和AI耐药性发展的影响。芳香酶表达的调节将在接受维生素D3治疗的妇女的组织库人类BCA样本中进行检测。研究设计：骨化三醇对BCA细胞株、原代正常乳腺和BCA细胞以及裸鼠BCA异种移植瘤的芳香化酶和PG途径基因及下游生物学反应的影响。机制研究将解决芳香酶启动子在BCA、脂肪、卵巢和骨细胞中的差异调节以及BCA细胞中ER1的调节。骨化三醇、人工智能及其组合对BCA生长的影响将在细胞培养和BCA的动物模型中进行评估。潜在的好处：拟议的研究将评估骨化三醇、人工授精及其联合治疗BCA患者的效果。骨化三醇和人工授精是经批准的药物，口服有效，安全，价格适中。我们预计这些发现将迅速将骨化三醇-AI组合推向临床试验，以治疗和/或预防BCA。公共健康相关性我们推测，骨化三醇加人工智能将显示出增强的活性，以防止BCA的生长和进展。我们相信，这项研究产生的数据将为支持骨化三醇-AI联合疗法迅速进入治疗BCA的临床试验铺平道路。这一策略将对BCA患者的常规治疗方案提供安全和经济的改进。

DESCRIPTION (provided by applicant): Calcitriol, the hormonally active form of vitamin D3, has well known anti-cancer activity. We have recently identified four novel pathways of additional calcitriol actions that inhibit breast cancer (BCa) growth. (1) Calcitriol directly inhibits aromatase expression in BCa cells and adipose tissue thereby reducing local estrogen synthesis and the major growth stimulus to estrogen receptor (ER) positive BCa cells. Importantly, calcitriol exhibits tissue specific regulation of aromatase causing down-regulation in BCa and adipose tissue and up-regulation in bone. The latter action would protect bone from the side effect of osteoporosis due to estrogen deprivation routinely seen in aromatase inhibitor (AI)-treated patients. (2) Calcitriol inhibits the synthesis of prostaglandins (PG), major stimulators of BCa growth, by multiple actions including suppression of COX-2 expression. (3) PGs are potent inducers of aromatase transcription in BCa and calcitriol's inhibition of PGs also indirectly reduces aromatase expression. (4) Calcitriol directly down-regulates ER1 expression. Thus calcitriol acts by multiple pathways to reduce the levels of both the ligand (estrogens) and the receptor (ER) and thereby suppress BCa growth. We postulate that calcitriol and AI combination therapy will improve AI efficacy, potency and safety, reduce osteoporosis risk and delay the development of AI-resistance. Objective: We will study these four pathways of calcitriol action and evaluate the effectiveness of the combination of calcitriol with AIs compared to individual drugs. These studies will rapidly pave the way to clinical trials of calcitriol-AI combination therapy in BCa patients. Specific Aims: Aim I examines calcitriol regulation of aromatase and PG pathway genes in BCa, adipose, ovary and bone cells and the effect of the calcitriol-AI combination to inhibit BCa cell growth. Aim II studies the mechanism for the differential regulation of aromatase. Aim III determines the mechanism by which calcitriol down-regulates ER1. In vivo studies in Aim IV assess the effects of calcitriol, AIs and their combinations in xenograft mouse models on tumor growth and the development of AI-resistance. Regulation of aromatase expression will be examined in tissue-banked human BCa specimens from women treated with vitamin D3. Study Design: Calcitriol effects on aromatase and PG pathway genes and down-stream biological responses will be studied in BCa cell lines, primary normal breast and BCa cells and BCa xenografts in nude mice. Mechanistic studies will address differential regulation of aromatase promoters in BCa, adipose, ovary and bone cells and ER1 in BCa cells. The effects of calcitriol, AIs and combinations on BCa growth will be assessed in cell culture and animal models of BCa. Potential Benefits: The proposed studies will evaluate calcitriol, AIs and combinations for therapy of BCa patients. Calcitriol and AIs are approved drugs, orally active, safe and are of modest cost. We expect these findings to swiftly advance calcitriol-AI combinations to clinical trials to treat and/or prevent BCa. PUBLICHEALTH RELEVANCE We postulate that calcitriol plus an AI will show enhanced activity to prevent the growth and progression of BCa. We believe the data generated by this study will pave the way to support the rapid advancement of calcitriol-AI combination therapy to clinical trials for the treatment of BCa. This strategy will provide a safe and economical improvement to the usual therapeutic regimen administered to BCa patients.