ISREC - Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Lausanne University Hospital, Lausanne, Switzerland.
EMBO Mol Med. 2021 Mar 5;13(3):e13180. doi: 10.15252/emmm.202013180. Epub 2021 Feb 22.
Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E-cadherin. It has clinical features distinct from other estrogen receptor-positive (ER ) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. Here, we recapitulate the human disease, including its metastatic pattern, by grafting ILC-derived breast cancer cell lines, SUM-44 PE and MDA-MB-134-VI cells, into the mouse milk ducts. Using patient-derived intraductal xenografts from lobular and non-lobular ER HER2 tumors to compare global gene expression, we identify extracellular matrix modulation as a lobular carcinoma cell-intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1. Treatment with the pan LOX inhibitor BAPN and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC.
浸润性小叶癌（ILC）是乳腺癌最常见的特殊组织学亚型，通常表现为 E-钙黏蛋白缺失。它具有与其他雌激素受体阳性（ER）乳腺癌不同的临床特征，但由于缺乏实验模型来研究其特征生物学，其潜在的分子机制仍不清楚。在这里，我们通过将来源于 ILC 的乳腺癌细胞系 SUM-44 PE 和 MDA-MB-134-VI 接种到小鼠乳腺导管中来重现人类疾病，包括其转移模式。使用来源于小叶和非小叶 ER HER2 肿瘤的患者源性管内异种移植来比较全基因表达，我们确定细胞外基质的调节是小叶癌细胞内在的特征。对 TCGA 患者数据集的分析表明，弹性蛋白、胶原蛋白和胶原蛋白修饰酶 LOXL1 的过表达使基质组学特征在小叶癌中富集。用泛 LOX 抑制剂 BAPN 治疗和沉默 LOXL1 的表达通过破坏 ECM 结构减少肿瘤生长、侵袭和转移，从而导致 ER 信号转导减少。我们得出结论，LOXL1 抑制是治疗 ILC 的一种有前途的治疗策略。
