Chemoprevention of cancer by nuclear receptor ligands

描述（由申请人提供）： 乳腺癌是女性中最常见的癌症之一，这种疾病每天都影响着许多女性的生活。由于疾病的最后阶段很难治愈，我们需要考虑不同的方法来克服这种疾病，例如早期预防。选择性雌激素受体调节剂（SERM）用于预防雌激素受体（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管理。然而，这些SERM在乳腺癌治疗中的益处仍然远未完全治愈，特别是对于ER阴性乳腺癌。我们一直有兴趣开发新的代理商的基础上，他们的作用机制，我们建议研究核受体及其配体的化学预防乳腺癌。维生素D受体（VDR）是核受体家族的一员，其配体参与了许多生物学过程的调节，包括乳腺、结肠、前列腺和其他器官中的细胞生长、分化和凋亡。尽管已经报道了维生素D类似物在许多癌细胞类型中抑制生长的能力，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。该提案的独特之处在于使用毒性降低的新型维生素D类似物进行研究，这些维生素D类似物具有独立于雌激素受体的作用，以及利用类似于并涵盖乳腺癌发生的不同谱的人MCF 10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型维生素D类似物预防乳腺癌的能力，并进一步研究维生素D类似物对这些细胞中转化生长因子-（TGF-β）/Smad信号传导的调节作用。该提案的目标是开发新型维生素D受体配体作为潜在的化学预防剂，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.