Gibson Shayin V, Tomas Bort Elena, Rodríguez-Fernández Lucía, Allen Michael D, Gomm Jennifer J, Goulding Iain, Auf dem Keller Ulrich, Agnoletto Andrea, Brisken Cathrin, Peck Barrie, Cameron Angus J, Marshall John F, Jones J Louise, Carter Edward P, Grose Richard P
Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.
Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark.
NPJ Breast Cancer. 2023 Mar 2;9(1):9. doi: 10.1038/s41523-023-00513-6.
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Virtually all women with DCIS are treated, despite evidence suggesting up to half would remain with stable, non-threatening, disease. Overtreatment thus presents a pressing issue in DCIS management. To understand the role of the normally tumour suppressive myoepithelial cell in disease progression we present a 3D in vitro model incorporating both luminal and myoepithelial cells in physiomimetic conditions. We demonstrate that DCIS-associated myoepithelial cells promote striking myoepithelial-led invasion of luminal cells, mediated by the collagenase MMP13 through a non-canonical TGFβ - EP300 pathway. In vivo, MMP13 expression is associated with stromal invasion in a murine model of DCIS progression and is elevated in myoepithelial cells of clinical high-grade DCIS cases. Our data identify a key role for myoepithelial-derived MMP13 in facilitating DCIS progression and point the way towards a robust marker for risk stratification in DCIS patients.
导管原位癌（DCIS）是浸润性乳腺癌的非必然前驱病变。实际上，所有患有DCIS的女性都接受了治疗，尽管有证据表明高达一半的患者病情会保持稳定、无威胁。因此，过度治疗是DCIS管理中一个紧迫的问题。为了了解正常情况下具有肿瘤抑制作用的肌上皮细胞在疾病进展中的作用，我们构建了一个三维体外模型，该模型在模拟生理条件下包含了管腔细胞和肌上皮细胞。我们证明DCIS相关的肌上皮细胞通过胶原酶MMP13介导的非经典TGFβ - EP300途径促进管腔细胞显著的肌上皮细胞主导的侵袭。在体内，MMP13表达与DCIS进展小鼠模型中的基质侵袭相关，并且在临床高级别DCIS病例的肌上皮细胞中升高。我们的数据确定了肌上皮来源的MMP13在促进DCIS进展中的关键作用，并为DCIS患者风险分层的可靠标志物指明了方向。
