Role of LSD1 in Triple Negative Breast Cancer Development and Therapeutic Response

项目摘要/摘要 乳腺癌是美国最常见的癌症，也是导致癌症死亡的第二大原因。 女人。大约10%-20%的乳腺癌是三阴性乳腺癌(TNBC)，它有发生 转移、复发并对化疗产生抗药性。TNBC是BC的唯一子类型，对于 没有针对性的治疗。化疗仍然是TNBC的主要治疗方法，但其临床疗效是 常常受到阻力的限制。免疫疗法正在成为TNBC患者一种令人兴奋的新治疗选择。 虽然TNBC对免疫治疗的反应更有可能，但总体应答率仍然很低。开发新的和 更有效的TNBC疗法是一种尚未满足的生物医学需求，因为大多数先进的TNBCs反应不佳 到目前的治疗方法。表观遗传改变，如DNA超甲基化和组蛋白失调 与TNBC形成和发展的所有阶段有关。赖氨酸特异性脱甲基酶1(LSD1)是第一个 确定组蛋白去甲基酶，特异性地去甲基化H3K4me1/2。LSD1是 转录抑制复合体。与TBC患者相比，TNBC患者的肿瘤经常表达更高水平的LSD1 给其他卑诗省的团体。临床上，LSD1蛋白过度表达与卵巢癌的预后显著相关。 TNBC患者，使其成为一个有吸引力的治疗目标。我们最近的研究揭示了一种新的机制 通过HDAC5介导的翻译后修饰推动LSD1蛋白在TNBC中过表达。 LSD1抑制剂治疗有效抑制肿瘤进展并使TNBC细胞对 化疗药物。此外，LSD1消融可刺激抗肿瘤免疫并增强 抗PD-1抗体对免疫原性差的TNBC的疗效。LSD1抑制导致关键字的重新表达 表观遗传沉默的肿瘤抑制基因，组织因子途径抑制物2(TFPI2)，这是 肿瘤抑制和免疫治疗的反应性。基于这些发现，我们假设LSD1 过表达促进TNBC的发展，抑制LSD1通过诱导 TFPI2介导的细胞杀伤和抗肿瘤免疫。目的：1.确定LSD1的功能角色 在TNBC发育中的过表达；AIM2。LSD1的体内外疗效评价 对TNBC的抑制作用；阐明LSD1抑制对TNBC的免疫原性作用。结果来自于 拟议的研究有望提供新的机制洞察力和关键的临床前证据，用于 TnBC中的LSD1抑制剂。从长远来看，这些研究可能会为患者带来新的和改进的治疗方法。 复发和难治性的TNBC。

PROJECT SUMMARY/ABSTRACT Breast cancer (BC) is the most common cancer and the second leading cause of cancer death in American women. About 10-20% of breast cancers are triple-negative breast cancer (TNBC), which has a propensity to metastasize, recur, and develop resistance to chemotherapy. TNBC is the only subtype of BC for which there is no targeted therapy. Chemotherapies remain the mainstay of treatment for TNBC, but their clinical efficacy is often limited by resistance. Immunotherapy is emerging as an exciting new treatment option for TNBC patients. While TNBC is more likely to respond to immunotherapy, overall response rate is still low. Developing novel and more effective TNBC therapies is an unmet biomedical need as most of advanced TNBCs do not respond well to current therapies. Epigenetic alterations such as DNA hypermethylation and histone dysregulation have been associated with all stages of TNBC formation and progression. Lysine-specific demethylase 1 (LSD1) is the first identified histone demethylase which specifically demethylates H3K4me1/2. LSD1 is a key component of multiple transcription repressor complexes. Tumors in TNBC patients frequently express higher level of LSD1 compared to other BC groups. Clinically, LSD1 protein overexpression is significantly associated with worse prognosis in TNBC patients, making it an attractive therapeutic target. Our recent study has revealed a new mechanism driving LSD1 protein overexpression in TNBC through HDAC5-mediated posttranslational modification. Treatment with LSD1 inhibitors effectively suppresses tumor progression and sensitizes TNBC cells to chemotherapeutic agents. Furthermore, LSD1 ablation stimulates antitumor immunity and potentiates the efficacy of anti-PD-1 antibody in poorly immunogenic TNBC. LSD1 inhibition leads to reexpression of a key epigenetically silenced tumor suppressor gene, Tissue Factor Pathway Inhibitor 2 (TFPI2), which is required for tumor suppression and responsiveness to immunotherapy. Based on these findings, we hypothesize that LSD1 overexpression facilitates TNBC development and inhibition of LSD1 improves TNBC therapies by inducing TFPI2-mediated cell killing and antitumor immunity. Aim1. Determine the functional roles of LSD1 overexpression in TNBC development; Aim2. Evaluate the in vitro and in vivo therapeutic efficacy of LSD1 inhibition against TNBC; Aim3. Elucidate the immunogenic effects of LSD1 inhibition in TNBC. The results from the proposed studies are expected to provide new mechanistic insights and key preclinical evidence for using LSD1 inhibitors in TNBC. In the long run, these studies may lead to new and improved therapies for patients with relapsed and refractory TNBC.