Nuclear receptor regulation of a breast cancer stem cell population

乳腺癌干细胞群的核受体调节

• 批准号: 9516953
• 负责人: Lynsey M Fettig Anderson
• 金额: $ 3.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9516953
• 关键词: Affect; Aromatase Inhibitors; Attenuated; Binding; Biological Assay; Breast; Breast Cancer Cell; Breast Cancer Prevention; Breast Cancer Treatment; Breast Cancer cell line; Cell Count; Cell Line; Cells; Cessation of life; Characteristics; Consensus; Cytokeratin; DNA Binding; Data; Dependence; Disease Outcome; Drug resistance; Endocrine; Estrogen Receptors; Estrogens; Exhibits; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Growth; Hormonal; Hormone replacement therapy; Hormones; Human; In Vitro; Laboratories; Luciferases; Malignant Neoplasms; Mammospheres; Mediating; Modeling; Mutate; Newly Diagnosed; Nuclear Receptors; Patients; Population; Postmenopause; Progesterone; Progesterone Receptors; Progestins; Promoter Regions; Property; Proteins; Recurrence; Regulation; Reporter; Resistance; Resistance development; Response Elements; Retinoic Acid Binding; Retinoic Acid Receptor; Retinoic Acid Response Element; Retinoids; Risk; Role; Signal Transduction; Stem cells; Structural Protein; T47D; Tamoxifen; Transcriptional Regulation; Treatment Efficacy; Tretinoin; Tumor Initiators; Tumorigenicity; United States; Woman; breast cancer diagnosis; cancer biomarkers; cancer cell; cancer diagnosis; cancer recurrence; cancer stem cell; chemotherapy; chromatin immunoprecipitation; cofactor; gene induction; gene repression; hormone therapy; improved; improved outcome; in vitro Assay; in vivo; knock-down; lifetime risk; malignant breast neoplasm; mortality; novel; overexpression; paracrine; prevent; progesterone receptor positive; promoter; protein expression; receptor binding; recruit; response; retinoic acid receptor alpha; retinoic acid receptor gamma; small hairpin RNA; small molecule; stem cell population; stem-like cell; stemness; theories; therapy development; therapy resistant; tumor; tumor initiation; tumor xenograft; tumorigenic

Project Summary Breast cancer is the most commonly diagnosed cancer in women in the United States with a 1 in 8 lifetime risk for most women. It also ranks second highest in cancer related mortality. Nearly 75% of newly diagnosed breast cancer cases are estrogen receptor (ER) and often progesterone receptor (PR) positive and therefore treated using targeted endocrine therapies such as Tamoxifen (Tam) and Aromatase Inhibitors (AIs). Unfortunately 40% of patients with ER+ breast cancer will acquire resistance to these therapies and have a tumor recurrence. While the role of estrogen in breast cancer has been extensively studied, the role of PR has been largely overlooked. Activation of PR via progestins in hormone replacement therapy has been shown to be associated with an increased risk of developing breast cancer in post-menopausal women. It has been theorized that this may be due to expansion of the stem cell populations in the normal breast, which are expanded in response to progestins and are more susceptible to transformation. In the normal breast, these stem and progenitor cell populations expanded by progesterone are marked by expression of cytokeratin 5 (CK5). Similarly, the Sartorius laboratory found that in ER+/PR+ breast cancer cell lines, progesterone can expand the CK5 expressing cell population, which has been shown to mark a cancer stem cell (CSC) population in these ER+/PR+ cell lines. The lab also found that this CK5 expressing population is more tumorigenic both in vitro and in vivo, and more resistant to chemo- and endocrine therapies. A small molecule screen performed by the lab determined that select retinoids, including retinoic acid (RA), are able to prevent the induction of CK5 seen following P4 treatment of breast cancer cells. It is not known, however, how RA is able to prevent the induction of CK5 or whether the expression of CK5 is necessary to confer these cancer stem cell-like properties. The studies proposed here will unravel the mechanism by which hormones positively or negatively regulate a CSC population within ER+PR+ breast cancer, and have the potential to identify a means to target this CSC population with the ultimate goal of reducing recurrence and improving the outcome of this disease.

项目摘要 乳腺癌是美国女性最常见的癌症，其终生风险为1/8。 对大多数女人来说。它在癌症相关死亡率中也排名第二。近75%的新诊断 乳腺癌病例是雌激素受体（ER）和经常是孕激素受体（PR）阳性， 使用靶向内分泌治疗，如他莫昔芬（Tam）和芳香酶抑制剂（AIs）。 不幸的是，40%的ER+乳腺癌患者将对这些治疗产生耐药性， 肿瘤复发虽然雌激素在乳腺癌中的作用已被广泛研究，但PR的作用仍有待进一步研究。 在很大程度上被忽视了。在激素替代疗法中，通过孕激素激活PR已被证明是 与绝经后妇女患乳腺癌的风险增加有关。已经 理论上，这可能是由于正常乳腺中干细胞群的扩增， 在孕激素的作用下会扩张，并且更容易转化。在正常的乳房中， 通过孕酮扩增的干细胞和祖细胞群通过细胞角蛋白5的表达来标记 （CK5）。同样，Sartorius实验室发现，在ER+/PR+乳腺癌细胞系中，孕酮可以 扩增CK 5表达细胞群，其已显示标记癌症干细胞（CSC） 在这些ER+/PR+细胞系中的群体。该实验室还发现，这种CK 5表达群体比其他人更容易表达。 在体外和体内都是致瘤的，并且对化疗和内分泌疗法更有抗性。小分子 实验室进行的一项筛选确定，包括维甲酸（RA）在内的某些类维生素A能够预防 P4处理乳腺癌细胞后观察到CK 5的诱导。然而，目前尚不清楚RA是如何 是否能够阻止CK 5的诱导或CK 5的表达是否是赋予这些癌症所必需的 干细胞样特性。这里提出的研究将揭示激素积极作用的机制。 或负调节ER+PR+乳腺癌中的CSC群体，并有可能鉴定出 以降低复发率和改善结局为最终目标的CSC人群为目标的方法 这种疾病的