Role of S100A7 in breast cancer progression and metastasis

描述（由申请人提供）：S100A7在ER？-浸润性癌，以及高级别导管原位癌（DCIS），因此可能在乳腺癌的进展和转移中起重要作用。我们的初步研究表明S100A7对ER？+和ER？——细胞;它能促进ER的生长和转移？抑制ER的生长？+乳腺癌细胞。然而，S100A7是否以及如何调节ER中的差异效应仍有待确定。+和ER？-乳腺癌亚型。我们的中心假设是，S100A7的差异效应是两种不同途径的结果：在内质网？-，它可能通过结合晚期糖基化终产物受体（RAGE）和反激活EGFR来调节肿瘤微环境；呃?+细胞，它可能调节2-catenin通路。患者的死亡率与ER的侵袭性显著相关。-特别是在三阴性乳腺癌中，以及雌激素受体耐药性的发展？+乳腺癌；因此，了解S100A7如何调节内质网的不同效应？-那急诊室呢？乳腺癌具有根本性的重要性。为此，我们将利用转基因和敲除小鼠模型系统，采用创新的、多学科的方法分析S100A7的作用和分子机制。在Aim 1中，我们将进一步分析S100A7在不同级别和亚型的乳腺癌组织微阵列中的表达，特别是三阴性乳腺癌。在Aim 2中，我们将进一步表征S100A7在调节ER生长和转移中的作用。+和ER？-体内小鼠模型中的细胞。在Aim 3中，我们将在转基因和敲除小鼠模型系统中分析S100A7在乳腺癌进展和转移中的作用。最后，在Aim 4中，我们将描述s100a7介导的促进ER？抑制细胞增殖和ER？+细胞。从这些研究中获得的见解可能有助于开发高侵入性ER的新颖和创新疗法。-和耐药ER？+乳腺癌。

DESCRIPTION (provided by applicant): S100A7 is highly expressed in ER?- invasive carcinoma, as well as in high grade ductal carcinomas in situ (DCIS), and therefore may play an important role in breast cancer progression and metastasis. Our preliminary studies indicate that S100A7 has differential effects on ER?+ and ER?- cells; it enhances growth and metastasis in ER?- and inhibits growth in ER?+ breast cancer cells. However, it remains to be determined if and how S100A7 modulates differential effects in ER?+ and ER?- breast cancer subtypes. Our central hypothesis is that the differential effects of S100A7 are a result of two different pathways: in ER?-, it may modulate the tumor microenvironment by binding to receptor for advance glycation end products (RAGE) and transactivating EGFR; in ER?+ cells, it may regulate the 2-catenin pathway. The mortality of patients is significantly caused by the invasive characteristics of ER?-, especially in triple-negative breast cancers, and the development of drug resistance in ER?+ breast cancers; as a result, understanding how S100A7 may modulate differential effects in ER?- and ER?+ breast cancers is of fundamental importance. To this end, we will use an innovative, multi-disciplinary approach to analyze the role and molecular mechanisms of S100A7, taking advantage of transgenic and knockout mouse model systems. In Aim 1, we will further analyze S100A7 expression in breast cancer tissue microarrays in different grades and subtypes, especially triple-negative breast cancers. In Aim 2, we will further characterize the role of S100A7 in modulating the growth and metastasis of ER?+ and ER?- cells in in vivo mouse models. In Aim 3, we will analyze the role of S100A7 in breast cancer progression and metastasis in transgenic and knockout mouse model systems. Finally, in Aim 4, we will delineate the S100A7-mediated molecular mechanisms that enhance growth and metastasis of ER?- cells and inhibit cell proliferation and migration of ER?+ cells. Insight gained from these studies may help in developing novel and innovative therapies for highly invasive ER?- and drug resistant ER?+ breast cancers.