npj Breast Cancer (Jan 2024)

Loss of the extracellular matrix glycoprotein EMILIN1 accelerates Δ16HER2-driven breast cancer initiation in mice

  • Andrea Favero,
  • Ilenia Segatto,
  • Alessandra Capuano,
  • Maria Chiara Mattevi,
  • Gian Luca Rampioni Vinciguerra,
  • Lorena Musco,
  • Sara D’Andrea,
  • Alessandra Dall’Acqua,
  • Chiara Gava,
  • Tiziana Perin,
  • Samuele Massarut,
  • Cristina Marchini,
  • Gustavo Baldassarre,
  • Paola Spessotto,
  • Barbara Belletti

DOI
https://doi.org/10.1038/s41523-023-00608-0
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 13

Abstract

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Abstract The extracellular matrix (ECM) is an important component of the tumor microenvironment and undergoes extensive remodeling during both initiation and progression of breast cancer (BC). EMILIN1 is an ECM glycoprotein, whose function has been linked to cancer and metastasis. However, EMILIN1 role during mammary gland and BC development has never been investigated. In silico and molecular analyses of human samples from normal mammary gland and BC showed that EMILIN1 expression was lower in tumors than in healthy mammary tissue and it predicted poor prognosis, particularly in HER2-positive BC. HER2+ BC accounts for 15-20% of all invasive BC and is characterized by high aggressiveness and poor prognosis. The Δ16HER2 isoform, a splice variant with very high oncogenic potential, is frequently expressed in HER2+ BC and correlates with metastatic disease. To elucidate the role of EMILIN1 in BC, we analyzed the phenotype of MMTV-Δ16HER2 transgenic mice, developing spontaneous multifocal mammary adenocarcinomas, crossed with EMILIN1 knock-out (KO) animals. We observed that Δ16HER2/EMILIN1 KO female mice exhibited an accelerated normal mammary gland development and a significantly anticipated appearance of palpable tumors (13.32 vs 15.28 weeks). This accelerated tumor initiation was corroborated by an increased number of tumor foci observed in mammary glands from Δ16HER2/EMILIN1 KO mice compared to the wild-type counterpart. Altogether our results underscore the centrality of ECM in the process of BC initiation and point to a role for EMILIN1 during normal mammary gland development and in protecting from HER2-driven breast tumorigenesis.