Emodin as a chemopreventive agent for breast cancer

摘要：乳腺癌是最常见的癌症，也是癌症相关死亡的第二大原因。 在美国的女性中。然而，在预防乳腺癌的发病率方面进展甚微。 癌症。大多数乳腺癌死亡是由于手术和/或手术初步成功后的转移复发所致。 其他疗法。尽管延长了选择性雌激素受体调节剂和芳香酶的治疗时间 抑制剂已被证明在预防乳腺癌转移复发方面有效，但益处有限。 对于ER+乳腺癌，严重的不良反应使其不适合长期使用。目前有 没有预防ER-乳腺癌的药物。考虑到高转移性复发率，这一点特别重要。 三阴性乳腺癌的发生率和由此导致的不良预后。乳腺癌的一个共同特征是， 无论亚型，都是亲肿瘤性质的肿瘤微环境，其中蕴含着丰富的 MΦS，称为肿瘤相关巨噬细胞(TAMs)。TAMs促进肿瘤的发展和转移 通过诱导免疫抑制、促进血管生成、促进肿瘤细胞增殖和 侵袭性，并促进癌症干细胞(CSC)的形成和维持。由于它们的决定因素 TAMs在癌症发展的所有阶段都发挥着作用，一直被认为是癌症的治疗靶点。 然而，MΦS尚未被用作乳腺癌预防的靶点。大黄素是一种小的 从许多植物中提取的分子化合物，包括几种中草药。我们发表的研究表明 大黄素通过降低M-Φ抑制小鼠原位乳腺癌的生长和转移 M-ΦS和乳房联合作用对肿瘤和肺的募集及抑制其类M2极化 癌细胞。我们的初步研究进一步表明，大黄素可以抑制转化生长因子β1诱导的上皮细胞 间质转化，减少乳腺癌细胞的干性，减少因 原位乳腺癌模型中手术切除原发肿瘤后的转移性复发。 重要的是，美国国立卫生研究院的一项综合毒理学研究表明，大黄素在小鼠身上长期使用是非常安全的 还有老鼠。鉴于MΦS在乳腺癌的发生和转移复发中的重要作用，并基于 根据我们已发表的和初步的数据，我们假设大黄素可以作为一种安全有效的 通过阻断乳腺癌的发生和转移复发的化学预防药物 肿瘤细胞与M-ΦS之间的促癌串扰。至 大黄素预防乳腺癌发病及术后转移复发的作用 小鼠模型和SA2。目的：阐明大黄素预防乳腺癌发生的机制。 转移复发。拟议的临床前研究的成功将为临床试验奠定基础 开发大黄素作为一种安全、有效、低成本的乳腺癌化学预防新药 子类型。

Summary: Breast cancer is the most prevalent cancer and the second leading cause of cancer-related death in women in the United States. However, little progress has been made in preventing the incidence of breast cancer. Most breast cancer mortality results from metastatic recurrence after initial success of surgery and/or other therapies. Although extended treatment with selective estrogen receptor modulators and aromatase inhibitors have been proven effective in preventing metastatic recurrence of breast cancer, the benefit is limited to ER+ breast cancer, and severe adverse effects make them suboptimal for long-term use. Currently there are no preventive agents for ER- breast cancer. This is of particular relevance given the high metastatic recurrence rate and the resulting poor prognosis of triple negative breast cancer. One common feature of breast cancer, regardless of the subtypes, is the pro-tumor nature of the tumor microenvironment, which contains abundant MΦs, called tumor-associated macrophages (TAMs). TAMs promote tumor development and metastasis through inducing immunosuppression, promoting angiogenesis, enhancing tumor cell proliferation and invasiveness, and facilitating cancer stem cell (CSC) formation and maintenance. Due to their determinant roles in all stages of cancer development, TAMs have been considered as a therapeutic target for cancer. However, MΦs have not yet been exploited as a target for breast cancer prevention. Emodin is a small molecule compound derived from many plants including several Chinese herbs. Our published studies showed that emodin inhibited breast cancer growth and metastasis in orthotopic mouse models through reducing MΦ recruitment to tumors and lungs and suppressing their M2-like polarization by acting on both MΦs and breast cancer cells. Our preliminary studies further showed that emodin could suppress TGFβ1-induced epithelial to mesenchymal transition and diminish the stemness of breast cancer cells, and reduce the death due to metastatic recurrence after surgical removal of primary tumors in an orthotopic breast cancer model. Importantly, a comprehensive NIH toxicology study showed that emodin is very safe for long-term use in mice and rats. Given the important roles of MΦs in breast cancer initiation and metastatic recurrence, and based on our published and preliminary data, we hypothesize that emodin can be developed as a safe and effective chemopreventive agent for breast cancer incidence and metastatic recurrence by virtue of its ability to block the tumor-promoting crosstalk between cancer cells and MΦs. Two specific aims are proposed: SA1. To determine the effects of emodin on preventing breast cancer onset and post-surgery metastatic recurrence in mouse models; and SA2. To elucidate the mechanisms by which emodin prevents breast cancer onset and metastatic recurrence. The success of the proposed preclinical studies will set a stage for clinical trials to develop emodin as a new safe, effective and low-cost chemopreventive agent for breast cancer regardless of the subtype.