Hormonal Regulation and Tumor Promotional Phenotypes of Semaphorin 7a in Breast Cancer

项目摘要/摘要 乳腺癌是最常见的癌症，也是与癌症相关的第二大病因。 美国女性死亡人数。超过一半的乳腺癌是激素受体阳性(HR+)，原因是 雌激素和/或孕激素受体(ER/PR)的表达。而针对ER的治疗是 通常在治疗原发肿瘤生长方面取得成功，高达40%的ER阳性肿瘤最终复发和 转移瘤。因此，需要新的分子靶点来治疗复发和转移的HR+乳腺 癌症。我们之前的研究发现Semaphorin 7a(SEMA7A)是一种多方面的介质 与HR+乳腺癌进展相关，包括增殖、侵袭和细胞存活。SEMA7A是 一种已知可以驱动神经元发育、免疫和纤维化的信号分子。SEMA7A是独一无二的 信号素家族的成员，因为它是唯一具有GPI锚的信号素，可以切割，允许 SEMA7A被释放到细胞外环境中。这支持了我的建议，即SEMA7A可能会影响 除了固有的细胞过程外，肿瘤的微环境也是如此。可供选择的多重宣传分析 乳腺癌患者队列中SEMA7A在乳腺肿瘤中的表达高于正常 乳房组织中SEMA7A的表达与存活率下降之间存在显著的相关性。已被占用 综上所述，这让我假设SEMA7A促进了乳腺癌的进展，可能是一种新的 治疗靶点。然而，SEMA7A表达增加背后的分子机制以及如何 导致肿瘤细胞侵袭性行为的SEMA7A信号仍不清楚。 该提案的目标是确定：1)SEMA7A在HR+乳腺癌中的表达是如何上调的， 2)SEMA7A信号如何促进细胞存活；3)SEMA7A是否通过 血管系统重塑。在目标1中，我将确定核激素受体是否直接 诱导SEMA7A的转录调控。我还将研究SEMA7A信号如何诱导观察到的 支持生存的表型。在目标2中，我将研究SEMA7A是否通过血管促进转移 改建。本研究的预期结果将进一步加深我们对SEMA7A表达和 HR+乳腺癌中的信号转导。这些结果将通过表征一种新的潜力而产生积极的影响 HR+乳腺癌的治疗靶点。最后，由于SEMA7A在大多数成人组织中最低限度地表达，我们 假设该疗法毒性低，是临床应用的理想方法。

Project Summary/Abstract Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-associated death in women in the United States. Over half of all breast cancers are hormone receptor positive (HR+), due to their expression of the estrogen and/or progesterone receptor (ER/PR). While ER-targeted therapies are typically successful at treating primary tumor growth, up to 40% of ER-positive tumors eventually recur and metastasize. Therefore, novel molecular targets are needed to treat recurrent and metastatic HR+ breast cancers. Our previous research identified Semaphorin 7a (SEMA7A) as a mediator of various aspects associated with HR+ breast cancer progression, including proliferation, invasion, and cell survival. SEMA7A is a signaling molecule known to drive neuronal development, immunity, and fibrosis. SEMA7A is a unique member of the semaphorin family, as it is the only semaphorin with a GPI-anchor that can be cleaved, allowing SEMA7A to be shed into the extracellular environment. This supports my proposal that SEMA7A may affect the tumor microenvironment in addition to inherent cellular processes. Analysis of multiple publicity available breast cancer patient cohorts revealed increased SEMA7A expression in breast tumors compared to normal breast tissue, as well as a significant correlation between SEMA7A expression and decreased survival. Taken together, this led me to hypothesize that SEMA7A promotes breast tumor progression and may be a novel therapeutic target. However, the molecular mechanisms behind increased SEMA7A expression and how SEMA7A signals to result in aggressive tumor cell behaviors remain unknown. The goals of this proposal are to determine: 1) how SEMA7A expression is upregulated in HR+ breast cancer, 2) how SEMA7A signaling promotes cell survival, and 3) whether SEMA7A promotes metastasis via remodeling of the blood vasculature. In aim 1, I will determine whether nuclear hormone receptors directly induce transcriptional regulation of SEMA7A. I will also examine how SEMA7A signals to induce the observed pro-survival phenotype. In aim 2, I will examine if SEMA7A promotes metastasis through blood vessel remodeling. The expected outcomes of this research will further our understanding of SEMA7A expression and signaling in HR+ breast cancer. These results will have a positive impact by characterizing a novel potential therapeutic target in HR+ breast cancer. Finally, as SEMA7A is minimally expressed in most adult tissues, we postulate this therapy will have low toxicity, making it ideal for clinical application.