Mechanisms of Breast Development and Carcinogenesis

描述(由申请人提供)：本申请提出了一项建议，将一项计划项目赠款延长至第三个五年资助期，该计划项目赠款支持波士顿-剑桥地区的互动研究小组网络，其研究重点是导致人类乳腺癌形成的遗传、分子和细胞机制。这项研究的结果越来越多地被应用于临床乳腺癌的发展、诊断和治疗问题。如下文所述，该计划在过去促进了参与研究小组之间的卓有成效的互动，并承诺在未来这样做。 过去在这些小组之间产生的协同作用以及在未来的资助期内提出的许多协同作用，都源于参与小组具有互补的利益，从而使用一些不同的实验方法来解决乳腺癌问题。这些互补策略包括：(I)BRCA1&2蛋白的缺陷如何导致DNA修复受损并导致乳腺癌；(Ii)D型细胞周期蛋白如何在多达一半的人类乳腺癌中驱动乳腺上皮细胞的增殖；(Iii)乳腺上皮细胞生物学的各种调节因子如何影响这些细胞的凋亡及其在乳腺癌发生早期的行为；(Iv)雌激素和孕激素受体如何影响乳腺上皮细胞的生物学；(V)乳腺癌细胞如何获得转移的能力并成功地发现远处组织部位的宏观转移；(Vi)基因表达模式的变化如何提供人类乳腺癌发展最初步骤的性质的迹象。这些办法的互补性在过去十年中产生了许多协作和相互促进的例子，并将在拟议的未来供资期间继续下去。 尽管在过去30年里进行了广泛的研究，但我们对不同类型的人类乳腺癌是如何开始的，充其量仍然只有零星的了解。导致这些肿瘤形成的机制必须在分子、细胞和最终组织水平上阐明。拟议的研究重点是了解导致乳腺癌发展的分子和细胞机制，因为很明显，只有在这些致病机制被发现的情况下，才能在未来开发出新的、真正有效的预后工具和治疗方法。因此，这里描述的一些研究方向如果成功，有可能建议开发新的、改进的诊断和治疗策略的方法，这些策略可以用于未来的乳腺癌临床。

DESCRIPTION (provided by applicant): This application presents a proposal to extend for a third five-year funding period a Program Project Grant that has supported a network of interacting research groups in the Boston-Cambridge area whose research is focused on the genetic, molecular, and cellular mechanisms leading to the formation of human breast cancers. The findings of this research are increasingly being applied and related to the problems of clinical breast cancer development, diagnosis, and treatment. As described below in this proposal, this Program has fostered fruitful interactions between the participating research groups in the past and promises to do so in the future. Much of the synergy that has arisen in the past among these groups and is proposed for the future funding period has derived from the fact that the participating groups have complementary interests, thereby attacking the breast cancer problem using a number of distinct experimental approaches. Included among these complementary strategies are studies of (I) how defects in the BRCA1&2 proteins lead to compromised DNA repair and resulting basaloid carcinomas of the breast; (ii) how D-type cyclins drive the proliferation of mammary epithelial cells in as many as half of human breast cancers; (iii) how various regulators of mammary epithelial cell biology affect the apoptosis of these cells and their behavior early in breast cancer development; (iv) how estrogen and progesterone receptors affect the biology of mammary epithelial cells; (v) how breast cancer cells acquire the ability to metastasize and succeed in founding macroscopic metastases at distant tissue sites; (vi) how changes of gene expression patterns provide indications of the nature of the initial steps of human breast cancer development. The complementarities of these approaches have led to many examples of collaboration and cross-fertilization over the past decade that will continue in the proposed future funding period. In spite of extensive research over the past three decades, we still possess, at best, only a fragmentary understanding of how the different types of human breast cancers begin. The mechanisms that lead to the formation of these tumors must be elucidated at the level of molecules, cells, and ultimately tissues. The proposed research is focused on understanding the molecular and cellular mechanisms leading to breast cancer development, because it is clear that novel, truly effective prognostic tools and therapies can only be developed in the future if these disease-causing mechanisms are uncovered. Accordingly, a number of the research directions described herein have the potential, if successful, to suggest approaches for developing novel, improved diagnostic arid therapeutic strategies that can be used in the breast cancer clinic of the future.