Roles of Hsp47 in breast cancer progression

尽管最近在早期诊断和辅助治疗方面取得了进展，但三阴性乳腺癌的治疗 癌症（TNBC）仍然是一个重大挑战，因为术后转移和复发率很高 治疗。来自细胞外基质 (ECM) 的信号，肿瘤微环境的重要组成部分， TNBC 进展和转移所必需的。然而，尚不清楚癌细胞沉积的 ECM 如何 癌细胞中的蛋白质和 ECM 信号传导受到调节并促进 TNBC 转移/复发。我们最近 确定 Hsp47 是 ECM 转录网络的枢纽。 Hsp47 是一种分子伴侣，调节 ECM 蛋白的分泌和沉积。在 TNBC 中检测到 Hsp47 表达增加，并且 与癌症转移有关。沉默 Hsp47 可抑制 3D 中 TNBC 细胞的侵袭性表型 培养并抑制异种移植模型中的肿瘤生长和肺定植，表明 Hsp47 增加 表达对于 TNBC 进展至关重要。 EMT通过增强癌细胞来促进癌症进展 传播并赋予癌细胞“干性”特性，有利于在细胞中成功定植 远处器官并有助于化学耐药性。癌细胞需要血小板粘附和激活 在远端部位定殖。我们发现沉默转移性乳腺癌细胞中的 Hsp47 可显着 血小板粘附减少。这些结果表明 Hsp47 通过诱导 TNBC 转移/复发 EMT 和血小板招募。在目标1中，我们将研究Hsp47调节的分子机制 EMT 和干性特性。在目标 2 中，我们将确定 Hsp47 促进的细胞机制 乳腺癌细胞在次要器官的定植。在目标 3 中，我们将定义 Hsp47 在以下方面的作用： 促进 TNBC 中的癌症转移和化疗耐药。这项调查将改变目前的情况 通过揭示癌细胞来源的胶原蛋白的新作用，提出癌症转移中 ECM 微环境的概念 诱导癌细胞-血小板相互作用和转移。 Hsp47 作为枢纽的表征 胶原蛋白/DDR2 信号传导将确定抑制 TNBC 进展和化疗耐药的新途径。

Despite recent advance in early diagnosis and adjuvant therapy, treatment of triple negative breast cancer (TNBC) remains a significant challenge because of the high incidence of metastasis and relapse after treatment. Signaling from extracellular matrix (ECM), an essential component of the tumor microenvironment, is required for TNBC progression and metastasis. However, it is not known how cancer cell-deposited ECM proteins and ECM signaling in cancer cells are regulated and promote TNBC metastasis/relapse. We recently identified Hsp47 as a hub of the ECM transcription network. Hsp47 is a molecular chaperon that regulates secretion and deposition of ECM proteins. Increased Hsp47 expression has been detected in TNBC and is associated with cancer metastasis. Silencing Hsp47 restrains the aggressive phenotype of TNBC cells in 3D culture and inhibits tumor growth and lung colonization in the xenograft model, indicating that increased Hsp47 expression is crucial for the TNBC progression. EMT promotes cancer progression by enhancing cancer cell dissemination and endowing cancer cells with “stemness” properties that favor successful colonization in distant organs and contribute to chemoresistance. Platelet adhesion and activation are required for cancer cell colonization at the distal sites. We found that silencing Hsp47 in metastatic breast cancer cells significantly reduced platelet adhesion. These results suggest that Hsp47 promotes TNBC metastasis/relapse by inducing EMT and platelet recruitment. In Aim 1, we will investigate the molecular mechanism by which Hsp47 regulates EMT and stemness properties. In Aim 2, we will determine the cellular mechanism by which Hsp47 promotes colonization of breast cancer cells at the secondary organs. In Aim 3, we will define the roles of Hsp47 in promoting cancer metastasis and chemoresistance in TNBC. This investigation will change the current concept of ECM microenvironment in cancer metastasis by revealing new roles of cancer cell-derived collagen in inducing cancer cell-platelet interaction and metastasis. Characterization of Hsp47 as a hub of collagen/DDR2 signaling will identify a novel pathway to inhibit TNBC progression and chemoresistance.