Chemoprevention of cancer by nuclear receptor ligands

描述(由申请人提供)： 乳腺癌是女性最常见的癌症之一，这种疾病每天都会影响到许多女性的生活。由于这种疾病的最后阶段很难治愈，我们需要考虑克服这种疾病的不同方法，例如早期预防。选择性雌激素受体调节剂(SERM)预防雌激素受体(ER)阳性乳腺癌的成功临床试验表明，预防方法有助于改善这种疾病的治疗。然而，这些SERM在治疗乳腺癌方面的益处仍然远远不能完全治愈，特别是对于ER阴性的乳腺癌。我们一直有兴趣开发基于其作用机制的新药物，我们建议研究一种核受体及其配体，用于乳腺癌的化学预防。维生素D受体(VDR)是核受体家族的一员，其配体参与调节乳腺、结肠、前列腺和其他器官的细胞生长、分化和凋亡等多种生物学过程。虽然维生素D类似物在多种癌细胞中抑制生长的能力已经被报道，但维生素D衍生物在ER阴性乳腺癌中的作用和作用机制仍有待研究。这项建议的独特之处在于，研究了毒性降低、作用不依赖雌激素受体的新型维生素D类似物，以及利用与乳腺癌发生的不同光谱相似并涵盖不同光谱的人类MCF10进行性乳腺癌模型。我们将在裸鼠体内异种移植模型中确定新的维生素D类似物预防乳腺癌的能力，并进一步研究维生素D类似物在调节这些细胞中转化生长因子(TGF-()/Smad)信号的作用。这项提议的目标是为维生素D受体开发新的配体，作为潜在的化学预防药物，最终可用于预防乳腺癌。

DESCRIPTION (provided by applicant): Breast cancer is one of the most commonly diagnosed cancers in women, and the disease affects many women's lives every day. Since the final stage of the disease is very difficult to cure, we need to consider different approaches to overcome this disease, such as prevention at an early stage. Preventive approaches, as shown by the successful clinical trials of selective estrogen receptor modulators (SERMs) for the prevention of estrogen receptor (ER) positive breast cancer, have contributed to improvement in the management of this disease. However, the benefit of these SERMs in the treatment of breast cancer is still far from a total cure, in particular with ER negative breast cancer. We have been interested in developing new agents based on their mechanisms of action, and we propose studying a nuclear receptor and its ligands for chemoprevention of breast cancer. The vitamin D receptor (VDR) is a member of the nuclear receptor family, and its ligands have been implicated in the regulation of many biological processes including cell growth, differentiation, and apoptosis in the breast, colon, prostate, and other organs. Although the ability of vitamin D analogs to arrest growth in many cancer cell types has been reported, the effects and the mechanisms of action of vitamin D derivatives in ER negative breast cancer remains to be investigated. Unique features of this proposal are studies with novel vitamin D analogs with decreased toxicity that have effects independent of estrogen receptor, and the utilization of the human MCF10 progressive breast cancer model that resembles and covers the different spectrum of breast carcinogenesis. We will determine the ability of novel vitamin D analogs to prevent breast cancer in an in vivo xenograft model using nude mice, and further investigate the role of the vitamin D analogs on the regulation of transforming growth factor-( (TGF-()/Smad signaling in these cells. The goal of this proposal is to develop novel ligands for the vitamin D receptor as potential chemopreventive agents that can ultimately be used to prevent breast cancer.