title: A preclinical mouse model of invasive lobular breast cancer metastasis.
abstract: Metastatic disease accounts for more than 90% of cancer-related deaths, but the development of effective antimetastatic agents has been hampered by the paucity of clinically relevant preclinical models of human metastatic disease. Here, we report the development of a mouse model of spontaneous breast cancer metastasis, which recapitulates key events in its formation and clinical course. Specifically, using the conditional K14cre;Cdh1(F/F);Trp53(F/F) model of de novo mammary tumor formation, we orthotopically transplanted invasive lobular carcinoma (mILC) fragments into mammary glands of wild-type syngeneic hosts. Once primary tumors were established in recipient mice, we mimicked the clinical course of treatment by conducting a mastectomy. After surgery, recipient mice succumbed to widespread overt metastatic disease in lymph nodes, lungs, and gastrointestinal tract. Genomic profiling of paired mammary tumors and distant metastases showed that our model provides a unique tool to further explore the biology of metastatic disease. Neoadjuvant and adjuvant intervention studies using standard-of-care chemotherapeutics showed the value of this model in determining therapeutic agents that can target early- and late-stage metastatic disease. In obtaining a more accurate preclinical model of metastatic lobular breast cancer, our work offers advances supporting the development of more effective treatment strategies for metastatic disease.
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Chris W
authors.initials: CW
authors.lastname: Doornebal
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Klarenbeek
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Braumuller
authors.forename: Christiaan N
authors.initials: CN
authors.lastname: Klijn
authors.forename: Metamia
authors.initials: M
authors.lastname: Ciampricotti
authors.forename: Cheei-Sing
authors.initials: CS
authors.lastname: Hau
authors.forename: Markus W
authors.initials: MW
authors.lastname: Hollmann
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Karin E
authors.initials: KE
authors.lastname: de Visser
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000235:genetics / Q000473:pathology*; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology*; D009368:Neoplasm Transplantation