Role of S100A7 in breast cancer progression and metastasis

描述(申请人提供)：S100A7在ER？浸润性癌和高级别导管原位癌中高表达，因此可能在乳腺癌的进展和转移中发挥重要作用。我们的初步研究表明，S100A7对ER？和ER？细胞；促进ER？细胞的生长和转移，抑制ER？细胞的生长？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。ER呢？-乳腺癌亚型。我们的中心假设是，S100A7的不同作用是两条不同途径的结果：在内质网中，它可能通过与晚期糖基化终产物受体(RAGE)结合和反式激活EGFR来调节肿瘤微环境；细胞，它可能调节2-连环蛋白途径。ER？-的侵袭性，尤其是三阴性乳腺癌的侵袭性是导致患者死亡的重要原因，ER？因此，了解S100A7可能如何调节ER？和ER？乳腺癌具有根本性的重要性。为此，我们将使用一种创新的、多学科的方法来分析S100A7的作用和分子机制，利用转基因和基因敲除小鼠模型系统。在目标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芯片中的表达，特别是三阴性乳腺癌。在目标2中，我们将进一步研究S100A7在调控ER？以及活体小鼠模型中的内质网？细胞。在目标3中，我们将在转基因和基因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，在目标4中，我们将阐述S100A7介导的促进ER？-细胞生长和转移、抑制ER？？细胞增殖和迁移的分子机制。细胞。从这些研究中获得的洞察力可能有助于开发治疗高侵袭性ER？和耐药ER？的新颖和创新疗法。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.