Role and Regulation of Id1 during Breast Cancer Metastasis Initiation

转移是乳腺癌患者发病的一个主要原因，因此加深对 这一进程背后的机制显然很重要。我们已经鉴定了一组蛋白质，称为ID 促进乳腺癌细胞在肺转移部位早期生长的蛋白质，其 乳腺癌中的过度表达与这些细胞保持未分化的能力有关， “茎状”状态。这些蛋白质似乎对抗间充质迁移状态，这种状态允许细胞进入 原发肿瘤最初从肿瘤块中分离出来，并通过血流传播。事实上，我们 假设ID蛋白允许循环中的乳腺癌细胞重新获得上皮样细胞 命运，由此促进了增长和殖民。在这项建议中，我们将探索这一机制 在这种情况下，ID蛋白通过识别受影响的蛋白来诱导这种“再集落”表型 直接或间接地通过ID。这一部分将是与琼·马萨格和菲利波·詹科蒂的合作。 此外，我们将确定在转移过程中ID本身上调的关键机制 过程在转化生长因子ȕ生长因子的调控下进行。这一部分将是与琼的合作 马萨格。最后，在确定了一个影响ID蛋白关联能力的小分子后 他们的靶蛋白，我们将尝试进一步开发这类新型的抗转移化合物。 在临床前模型中的有效性。本部分将与尼尔·罗森、拉里·诺顿和琼合作 马萨格。

Metastasis is a major cause of morbidity in breast cancer patients so a deeper understanding of the mechanisms underlying this process is of obvious importance. We have identified a set of proteins, called Id proteins, which facilitate the early stages of breast cancer cell growth in the lung metastatic site and whose overexpression in breast cancer is associated with the ability of these cells to remain in an undifferentiated, "stem-like" state. These proteins appear to antagonize the mesenchymal, migratory state that allow cells in the primary tumor to initially break off from the tumor bulk and travel through the blood stream. Indeed, we postulate here that the Id proteins allow for breast cancer cells in circulation to reacquire an epithelial-like fate whereby growth and colonization are facilitated. In this proposal we will explore the mechanism whereby the Id proteins induce this "recolonization" phenotype by identifying the proteins that are affected by Id directly and indirectly. This section will be a collaboration with Joan Massague and Filippo Giancotti. In addition , we will identify the key mechanisms whereby Id itself is upregulated during the metastatic process under the control of the TGFȕ growth factor. This section will be a collaboration with Joan Massague. Finally, having identified a small molecule the affects the ability of Id proteins to associate with their target proteins, we will attempt to further develop this novel class of compounds for anti-metastatic efficacy in pre-clinical models. This section will be a collaboration with Neal Rosen, Larry Norton and Joan Massague.