Mouse & Human Models of Breast Development and Neoplasia

试图了解乳腺癌发病机制的详细分子机制，部分是由于缺乏充分概括正常和肿瘤人类乳腺组织的生物学属性的实验模型而受挫。这一缺陷激发了在免疫功能低下的小鼠中构建人类乳腺组织的灵感，该组织似乎以与正常人类乳腺非常相似的方式起作用。随着该模型的可用性，可以检查被认为参与人类乳腺发病机制的各种基因的精确生物学和形态发生作用。导致人类乳腺上皮细胞增生的机制仍然知之甚少。垂体来源的催乳素（Prl）通常参与促进妊娠后期乳腺的发育。要进行的研究将检查Prl如何能够 引起代表肿瘤进展早期阶段的乳腺上皮组织病理学改变。已经开发的基因改变的小鼠模型将被证明在阐明由配体激活的Prl受体直接诱导的乳腺上皮细胞（MEC）中的生化变化方面非常有用。第三条研究路线涉及使致瘤但非侵入性MEC获得使这些细胞能够侵入和转移的特征的分子机制。 三个转录因子（TF）的特点是能够激活上皮间充质转化（EMT），这似乎是密切相关的收购能力的MEC入侵，然后转移。详细的研究将集中在这里，特别是在Goosecoid TF。一方面，这种TF的表达可以通过TGF在上皮细胞中诱导，TGF是一种经常与原发性肿瘤的侵袭性前沿相关的蛋白质。另一方面，Goosecoid能够编程许多与EMT相关的变化，包括上皮标记物的丢失，间充质标记物的获得和运动性的增加。Goosecoid与两个 将探索类似地起作用的其它TF，以试图确定涉及这三种TF的单个信号传导回路是否负责编程所有类型的癌症相关侵袭性，或者不同的TF是否与人类MEC中不同的侵袭控制调节回路相关。

Attempts at understanding the detailed molecular mechanisms of breast cancer pathogenesis have been frustrated in part by the lack of experimental models that adequately recapitulate the biological attributes of normal and neoplastic human breast tissues. This shortcoming has inspired the construction of human mammary gland tissue in immunocompromised mice that appears to function in a fashion that closely resembles that of the normal human mammary gland. With the availability of this model, the precise biological and morphogenetic actions of various genes that are thought to participate in human breast pathogenesis can be examined. The mechanisms that lead to the hyperplasias seen in the human breast epithelium are still poorly understood. Prolactin (Prl) of pituitary origin is normally involved in promoting the development of the mammary gland late in pregnancy. Research to be conducted examines how Prl is able to elicit histopathological alterations in the mammary epithelium that represent early steps of tumor progression. A genetically altered mouse model that has been developed will prove highly useful in elucidating the biochemical changes in mammary epithelial cells (MECs) that are directly induced by the ligand-activated Prl receptor. A third line of research addresses the molecular mechanisms that enable tumorigenic but non-invasive MECs to acquire the traits that enable such cells to invade and metastasize. Three transcription factors (TFs) have been characterized that are capable of activating the epithelial-tomesenchymal transformation (EMT) that appears to be closely linked to the acquired ability of MECs to invade and thereafter to metastasize. Detailed research will be focused here specifically on the Goosecoid TF. On the one hand, expression of this TF can be induced in epithelial cells by TGF, a protein that has frequently been associated with the invasive front of primary tumors. On the other, Goosecoid is capable of programming many of the changes associated with the EMT, including loss of epithelial markers, acquisition of mesenchymal markers, and increased motility. The functional relationships between Goosecoid and two other TFs that function analogously will be explored in an attempt to determine whether a single signaling circuit involving these three TFs is responsible for programming all types of cancer-associated invasiveness, or whether different TFs are associated with distinct invasion-controlling regulatory circuits in human MECs.