Publication

Intraductal xenografts show lobular carcinoma cells rely on their own extracellular matrix and LOXL1

Résumé

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.

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Concepts associés (32)
Cancer du sein
Le 'cancer du sein' est un cancer de la glande mammaire. Autrement dit, c'est un cancer qui naît dans les unités cellulaires dont la fonction est de sécréter le lait, les unités ducto-lobulaires du sein, essentiellement chez la femme. Huit cancers du sein sur dix se déclarent après 50 ans. Premier cancer dans le monde, il touche, en 2016, 1,8 million de femmes par an dans le monde, dont en France. On s'attend à ce qu'une femme sur huit reçoive un diagnostic de cancer du sein au cours de sa vie.
Carcinome lobulaire in situ
Un carcinome lobulaire in situ (CLIS) est une zone de croissance anormale des cellules épithéliales d'un lobule du sein. Il peut se résorber ou rester stable, ou quelquefois évoluer vers un cancer du sein de type canalaire ou lobulaire, mais n'est pas considéré comme étant un cancer ni même un état pré-cancéreux. C'est un facteur de risque de cancer du sein invasif, bien qu'il soit regroupé parmi les carcinomes in situ du sein. C'est un indicateur de dépistage précoce du cancer du sein.
Breast cancer classification
Breast cancer classification divides breast cancer into categories according to different schemes criteria and serving a different purpose. The major categories are the histopathological type, the grade of the tumor, the stage of the tumor, and the expression of proteins and genes. As knowledge of cancer cell biology develops these classifications are updated. The purpose of classification is to select the best treatment. The effectiveness of a specific treatment is demonstrated for a specific breast cancer (usually by randomized, controlled trials).
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