Nuclear receptor regulation of a breast cancer stem cell population

项目摘要 乳腺癌是美国女性最常见的确诊癌症，一生中有1/8的风险 对大多数女性来说。它也是与癌症相关的死亡率第二高的国家。近75%的新诊断 乳腺癌患者雌激素受体(ER)和孕激素受体(PR)呈阳性，因此 使用靶向内分泌治疗，如三苯氧胺()和芳香酶抑制剂(AIs)。 不幸的是，40%的ER+乳腺癌患者会对这些治疗产生抵抗力，并有 肿瘤复发。虽然雌激素在乳腺癌中的作用已经被广泛研究，但PR的作用已经 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 与绝经后妇女罹患乳腺癌的风险增加有关。一直以来 推测这可能是由于正常乳房中干细胞数量的增加，这是 对孕激素的反应而膨胀，更容易转化。在正常的乳房中，这些 孕酮扩增的干细胞和祖细胞群以细胞角蛋白5的表达为标志 (第五条)。同样，萨托利斯实验室发现，在ER+/PR+乳腺癌细胞系中，黄体酮可以 扩大表达CK5的细胞群，这已被证明是标记癌症干细胞(CSC) 在这些ER+/PR+细胞系中的群体。实验室还发现，这个表达CK5的人群比 在体外和体内都有致癌作用，对化疗和内分泌治疗更具抵抗力。一种小分子 实验室进行的筛查确定，包括维甲酸(RA)在内的部分维甲酸能够预防 乳腺癌细胞P4处理后CK5的诱导。然而，目前还不知道RA是如何形成的 能够阻止CK5的诱导或CK5的表达是否是诱发这些癌症所必需的 干细胞样的特性。这里提出的研究将揭开荷尔蒙积极作用的机制 或负向调节ER+PR+乳腺癌内的CSC群体，并有可能识别出 以CSC人群为目标，最终目标是减少复发和改善结果的手段 这种疾病。

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.