Role of S100A7 in breast cancer progression and metastasis

描述（申请人提供）：S100 A7在ER？中高度表达。浸润性癌以及高级别导管原位癌（DCIS）中，并且因此可能在乳腺癌进展和转移中起重要作用。我们的初步研究表明，S100 A7对ER？+而ER？细胞;它增强ER？的生长和转移。并抑制ER？+的生长乳腺癌细胞然而，S100 A7是否以及如何调节ER？+中的差异效应仍有待确定。而ER？乳腺癌亚型。我们的中心假设是，S100 A7的不同作用是两种不同途径的结果：在ER？-，它可能通过与晚期糖基化终产物受体（receptor for advanced glycation end products，EGFR）结合和反式激活EGFR来调节肿瘤微环境;细胞，它可以调节2-catenin途径。ER？-的侵袭性是导致患者死亡的重要原因，尤其是在三阴性乳腺癌中，以及ER？+乳腺癌;因此，了解S100 A7如何调节ER？所以，+？乳腺癌具有根本重要性。为此，我们将采用创新的多学科方法，利用转基因和基因敲除小鼠模型系统，分析S100 A7的作用和分子机制。目的1：进一步分析S100 A7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。在目的2中，我们将进一步表征S100 A7在调节ER？+细胞生长和转移中的作用。而ER？在体内小鼠模型中的细胞。在目标3中，我们将分析S100 A7在转基因和敲除小鼠模型系统中在乳腺癌进展和转移中的作用。最后，在目标4中，我们将描述S100 A7介导的增强ER？细胞和抑制细胞增殖和迁移的ER？+细胞从这些研究中获得的见解可能有助于开发用于高度侵入性ER？的新型和创新疗法。和耐药ER？+乳腺癌 公共卫生相关性：S100 A7在侵袭性ER？和高级别导管原位癌（DCIS）乳腺癌亚型。然而，关于它在乳腺癌的发展和进展中的作用知之甚少。这些研究将确定S100 A7增强ER？-1细胞生长和转移的分子机制。并抑制ER？+的生长细胞了解S100 A7在ER中的不同作用？所以，+？乳腺癌可能为预防和治疗高度侵袭性和难以治疗的ER？乳腺癌，以及ER？+耐药乳腺癌此外，这些研究还将提供有关S100 A7在不同级别和类型的乳腺癌中表达的信息，特别是ER？基底型乳腺癌

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. PUBLIC HEALTH RELEVANCE: S100A7 is highly expressed in both the aggressive ER?- and high grade ductal carcinoma in situ (DCIS) breast cancer subtypes. However, not much is known about its role in the development and progression of breast cancer. The proposed studies will determine the molecular mechanism by which S100A7 enhances growth and metastasis in ER?- and inhibits growth in ER?+ cells. Understanding the differential role of S100A7 in ER?- and ER?+ breast cancers may provide novel insights for prevention and treatment of highly aggressive and difficult to treat ER?- breast cancers, as well as ER?+ drug resistant breast cancers. In addition, these studies will also provide information about S100A7 expression in different grades and types of breast cancers, especially ER?- basal-type breast cancers.