Original Paper
A mouse model of basal‐like breast carcinoma with metaplastic elements*
*
No conflicts of interest were declared.
Abstract
Breast cancers arising in carriers of germline BRCA1 mutations frequently have a basal‐like phenotype. Basal‐like cancers are characterized by high histological grade, central necrotic areas, foci with metaplastic differentiation, lack of hormone receptor and HER2 (ErbB2) expression, and consistent positivity for basal markers, including CK5/6, CK14, and EGFR. We have used germline manipulation to generate a conditional mouse model of Brca1 deficiency. Transgenic expression of Cre recombinase in the mammary gland of these mice results in deletion of exons encoding the C‐terminus of Brca1 and leads to tumour formation when combined with heterozygosity for a p53 mutation. Histologically, these mammary gland tumours were characterized by high histological grade, central necrotic areas, and presence of homologous metaplastic elements. These metaplastic elements consisted of neoplastic spindle cells or squamous cell differentiation in the form of keratin pearls or individual cell keratinization. Immunohistochemical analysis revealed expression of basal‐like markers in all cases. The tumour phenotype generated in our mouse model was compared with published data on human basal‐like breast carcinomas and also with metaplastic breast cancers with a basal‐like phenotype; the comparison showed that we have generated a mouse model of basal‐like breast cancer, which should prove useful in testing new and targeted treatments for this type of breast cancer. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Citing Literature
Number of times cited: 63
- Emad Rakha, Metaplastic Breast Carcinomas, Breast Pathology, 10.1007/978-3-319-28655-6_12, (153-166), (2016).
- Iwona K. Rzepecka, Lukasz M. Szafron, Agnieszka Stys, Anna Felisiak-Golabek, Agnieszka Podgorska, Agnieszka Timorek, Piotr Sobiczewski, Barbara Pienkowska-Grela, Mona El-Bahrawy and Jolanta Kupryjanczyk, Prognosis of patients with BRCA1 -associated ovarian carcinomas depends on TP53 accumulation status in tumor cells, Gynecologic Oncology, 144, 2, (369), (2017).
- Jonathan Rennhack, Briana To, Harrison Wermuth and Eran R. Andrechek, Mouse Models of Breast Cancer Share Amplification and Deletion Events with Human Breast Cancer, Journal of Mammary Gland Biology and Neoplasia, 22, 1, (71), (2017).
- Victoria E. Mgbemena, Robert A.J. Signer, Ranjula Wijayatunge, Travis Laxson, Sean J. Morrison and Theodora S. Ross, Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function, Cell Reports, 18, 4, (947), (2017).
- Yoshihiro Hayakawa, Manabu Kawada, Hiroyoshi Nishikawa, Takahiro Ochiya, Hideyuki Saya, Hiroyuki Seimiya, Ryoji Yao, Masahiro Hayashi, Chieko Kai, Akira Matsuda, Tomoki Naoe, Atsushi Ohtsu, Taku Okazaki, Hideo Saji, Masataka Sata, Haruhiko Sugimura, Yuichi Sugiyama, Masakazu Toi and Tatsuro Irimura, Report on the use of non‐clinical studies in the regulatory evaluation of oncology drugs, Cancer Science, 107, 2, (189-202), (2016).
- A. Vasanthakumar, S. Arnovitz, R. Marquez, J. Lepore, G. Rafidi, A. Asom, M. Weatherly, E. M. Davis, B. Neistadt, R. Duszynski, J. W. Vardiman, M. M. Le Beau, L. A. Godley and J. E. Churpek, Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice, Blood, 127, 3, (310), (2016).
- Britta Weigelt, Charlotte K Y Ng, Ronglai Shen, Tatiana Popova, Michail Schizas, Rachael Natrajan, Odette Mariani, Marc-Henri Stern, Larry Norton, Anne Vincent-Salomon and Jorge S Reis-Filho, Metastatic breast carcinomas display genomic and transcriptomic heterogeneity, Modern Pathology, 28, 3, (340), (2015).
- Hsuan-Shun Huang, Sung-Chao Chu, Che-Fang Hsu, Pao-Chu Chen, Dah-Ching Ding, Meng-Ya Chang and Tang-Yuan Chu, Mutagenic, surviving and tumorigenic effects of follicular fluid in the context of p53 loss: initiation of fimbria carcinogenesis, Carcinogenesis, 36, 11, (1419), (2015).
- Kirsty R. Greenow and Matthew J. Smalley, Overview of Genetically Engineered Mouse Models of Breast Cancer Used in Translational Biology and Drug Development, Current Protocols in Pharmacology, 70, 1, (14.36.1-14.36.14), (2015).
- Lorenzo Melchor, Gemma Molyneux, Alan Mackay, Fiona‐Ann Magnay, María Atienza, Howard Kendrick, Daniel Nava‐Rodrigues, María Ángeles López‐García, Fernanda Milanezi, Kirsty Greenow, David Robertson, José Palacios, Jorge S Reis‐Filho and Matthew J Smalley, Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models, The Journal of Pathology, 233, 2, (124-137), (2014).
- Daniel P Hollern and Eran R Andrechek, A genomic analysis of mouse models of breast cancer reveals molecular features ofmouse models and relationships to human breast cancer, Breast Cancer Research, 10.1186/bcr3672, 16, 3, (2014).
- Walid T. Khaled and Pentao Liu, Cancer mouse models: Past, present and future, Seminars in Cell & Developmental Biology, 27, (54), (2014).
- Jennifer Dine and Chu-Xia Deng, Mouse models of BRCA1 and their application to breast cancer research, Cancer and Metastasis Reviews, 32, 1-2, (25), (2013).
- JOSEFA SALGADO, MARTA SANTISTEBAN, CRISTINA GUTIÉRREZ, CARMEN GIL, MAITANE ROBLES, ADRIANA VIEDMA and ANA PATIÑO-GARCÍA, A novel BRCA1 mutation in a patient with breast and ovarian cancer: A case report, Oncology Letters, 6, 3, (725), (2013).
- Marketa Zvelebil, Erik Oliemuller, Qiong Gao, Olivia Wansbury, Alan Mackay, Howard Kendrick, Matthew J Smalley, Jorge S Reis-Filho and Beatrice A Howard, Embryonic mammary signature subsets are activated in Brca1 -/- and basal-like breast cancers, Breast Cancer Research, 15, 2, (2013).
- Aziza Nassar, Zachary M Sussman, Diane Lawson and Cynthia Cohen, Inference of the Basal Epithelial Phenotype in Breast Carcinoma from Differential Marker Expression, Using Tissue Microarrays in Triple Negative Breast Cancer and Women Younger than 35, The Breast Journal, 18, 5, (399-405), (2012).
- Magali Lacroix-Triki, Felipe C. Geyer, Britta Weigelt and Jorge S. Reis-Filho, Triple-Negative and Basal-like Carcinoma, Breast Pathology, 10.1016/B978-1-4377-0604-8.00024-2, (446-478), (2012).
- Manuela Santarosa and Roberta Maestro, BRACking news on triple-negative/basal-like breast cancers: how BRCA1 deficiency may result in the development of a selective tumor subtype, Cancer and Metastasis Reviews, 31, 1-2, (131), (2012).
- Ewa Malgorzata Michalak and Jos Jonkers, Studying Therapy Response and Resistance in Mouse Models for BRCA1-Deficient Breast Cancer, Journal of Mammary Gland Biology and Neoplasia, 16, 1, (41), (2011).
- Gemma Molyneux and Matthew J. Smalley, The Cell of Origin of BRCA1 Mutation-associated Breast Cancer: A Cautionary Tale of Gene Expression Profiling, Journal of Mammary Gland Biology and Neoplasia, 16, 1, (51), (2011).
- Gulisa Turashvili, Steven E McKinney, Ozge Goktepe, Samuel C Leung, David G Huntsman, Karen A Gelmon, Gerrit Los, Paul A Rejto and Samuel A J R Aparicio, P-cadherin expression as a prognostic biomarker in a 3992 case tissue microarray series of breast cancer, Modern Pathology, 10.1038/modpathol.2010.189, 24, 1, (64-81), (2010).
- David H. Nguyen, Hellen A. Oketch-Rabah, Irineu Illa-Bochaca, Felipe C. Geyer, Jorge S. Reis-Filho, Jian-Hua Mao, Shraddha A. Ravani, Jiri Zavadil, Alexander D. Borowsky, D. Joseph Jerry, Karen A. Dunphy, Jae Hong Seo, Sandra Haslam, Daniel Medina and Mary Helen Barcellos-Hoff, Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type, Cancer Cell, 19, 5, (640), (2011).
- Britta Weigelt, Frederick L Baehner and Jorge S Reis‐Filho, The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade, The Journal of Pathology, 220, 2, (263-280), (2009).
- Gianluca Storci, Pasquale Sansone, Sara Mari, Gabriele D'Uva, Simona Tavolari, Tiziana Guarnieri, Mario Taffurelli, Claudio Ceccarelli, Donatella Santini, Pasquale Chieco, Kenneth B. Marcu and Massimiliano Bonafè, TNFalpha up‐regulates SLUG via the NF‐kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell‐like phenotype, Journal of Cellular Physiology, 225, 3, (682-691), (2010).
- Jiaxue Wu, Lin-Yu Lu and Xiaochun Yu, The role of BRCA1 in DNA damage response, Protein & Cell, 1, 2, (117), (2010).
- H. Mizuno, B. T. Spike, G. M. Wahl and A. J. Levine, Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures, Proceedings of the National Academy of Sciences, 107, 52, (22745), (2010).
- Katja Gwin, Darren T. Wheeler, Veerle Bossuyt and Fattaneh A. Tavassoli, Breast Carcinoma With Chondroid Differentiation: A Clinicopathologic Study of 21 Triple Negative (ER−, PR−, Her2/neu−) Cases, International Journal of Surgical Pathology, 18, 1, (27), (2010).
- Sohail Jahid and Steven Lipkin, Mouse Models of Inherited Cancer Syndromes, Hematology/Oncology Clinics of North America, 10.1016/j.hoc.2010.08.011, 24, 6, (1205-1228), (2010).
- M. Quintela-Fandino, E. Arpaia, D. Brenner, T. Goh, F. A. Yeung, H. Blaser, R. Alexandrova, E. F. Lind, M. W. Tusche, A. Wakeham, P. S. Ohashi and T. W. Mak, HUNK suppresses metastasis of basal type breast cancers by disrupting the interaction between PP2A and cofilin-1, Proceedings of the National Academy of Sciences, 107, 6, (2622), (2010).
- Anastasia Constantinidou, Robin L Jones and Jorge S Reis-Filho, Beyond triple-negative breast cancer: the need to define new subtypes, Expert Review of Anticancer Therapy, 10, 8, (1197), (2010).
- Junko Sugiyama, Motoo Yamagata, Tomohisa Kamo, Kazuo Sato, Tomoaki Takasugi, Mistuko Kasahara, Masashi Fujii, Tadatosi Takayama and Noriko Kinukawa, A Case of Matrix-producing Carcinoma of the Breast, Journal of Nihon University Medical Association, 69, 5, (310), (2010).
- Gemma Molyneux, Felipe C. Geyer, Fiona-Ann Magnay, Afshan McCarthy, Howard Kendrick, Rachael Natrajan, Alan MacKay, Anita Grigoriadis, Andrew Tutt, Alan Ashworth, Jorge S. Reis-Filho and Matthew J. Smalley, BRCA1 Basal-like Breast Cancers Originate from Luminal Epithelial Progenitors and Not from Basal Stem Cells, Cell Stem Cell, 7, 3, (403), (2010).
- Anna L. Stratford, Kristen Reipas, Christopher Maxwell and Sandra E. Dunn, Targeting tumour-initiating cells to improve the cure rates for triple-negative breast cancer, Expert Reviews in Molecular Medicine, 10.1017/S1462399410001535, 12, (2010).
- Andrey I. Khramtsov, Galina F. Khramtsova, Maria Tretiakova, Dezheng Huo, Olufunmilayo I. Olopade and Kathleen H. Goss, Wnt/β-Catenin Pathway Activation Is Enriched in Basal-Like Breast Cancers and Predicts Poor Outcome, The American Journal of Pathology, 176, 6, (2911), (2010).
- Jean-Christophe Noël, Frédéric Buxant and Corinne Engohan-Aloghe, Low-grade adenosquamous carcinoma of the breast—A case report with a BRCA1 germline mutation, Pathology - Research and Practice, 206, 7, (511), (2010).
- Britta Weigelt, Felipe C. Geyer and Jorge S. Reis-Filho, Histological types of breast cancer: How special are they?, Molecular Oncology, 4, 3, (192-208), (2010).
- Afshan McCarthy, Christopher J Lord, Kay Savage, Anita Grigoriadis, Darrin P Smith, Britta Weigelt, Jorge S Reis‐Filho and Alan Ashworth, Conditional deletion of the Lkb1 gene in the mouse mammary gland induces tumour formation, The Journal of Pathology, 219, 3, (306-316), (2009).
- Emad A. Rakha, Maysa E. El-Sayed, Jorge Reis-Filho and Ian O. Ellis, Patho-biological aspects of basal-like breast cancer, Breast Cancer Research and Treatment, 113, 3, (411), (2009).
- Janneke E. Jaspers, Sven Rottenberg and Jos Jonkers, Therapeutic options for triple-negative breast cancers with defective homologous recombination, Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 10.1016/j.bbcan.2009.07.001, 1796, 2, (266-280), (2009).
- Felipe C. Geyer, Maria A. Lopez‐Garcia, Maryou B. Lambros and Jorge S. Reis‐Filho, Genetic characterization of breast cancer and implications for clinical management, Journal of Cellular and Molecular Medicine, 13, 10, (4090-4103), (2009).
- R M Drost and J Jonkers, Preclinical mouse models for BRCA1-associated breast cancer, British Journal of Cancer, 101, 10, (1651), (2009).
- Britta Weigelt, Bas Kreike and Jorge S. Reis-Filho, Metaplastic breast carcinomas are basal-like breast cancers: a genomic profiling analysis, Breast Cancer Research and Treatment, 117, 2, (273), (2009).
- Britta Weigelt and Jorge S. Reis-Filho, Histological and molecular types of breast cancer: is there a unifying taxonomy?, Nature Reviews Clinical Oncology, 6, 12, (718), (2009).
- Takashi Takeshita, Wenwen Wu, Ayaka Koike, Mamoru Fukuda and Tomohiko Ohta, Perturbation of DNA repair pathways by proteasome inhibitors corresponds to enhanced chemosensitivity of cells to DNA damage-inducing agents, Cancer Chemotherapy and Pharmacology, 64, 5, (1039), (2009).
- Tomohiko Ohta, Wenwen Wu, Ayaka Koike, Hideki Asakawa, Hirotaka Koizumi and Mamoru Fukuda, Contemplating chemosensitivity of basal-like breast cancer based on BRCA1 dysfunction, Breast Cancer, 16, 4, (268), (2009).
- Barry Gusterson, Do 'basal-like' breast cancers really exist?, Nature Reviews Cancer, 9, 2, (128), (2009).
- Felipe C. Geyer, Caterina Marchiò and Jorge S. Reis-Filho, The role of molecular analysis in breast cancer, Pathology, 10.1080/00313020802563536, 41, 1, (77-88), (2009).
- Felipe Correa Geyer and Jorge Sergio Reis-Filho, Microarray-based Gene Expression Profiling as a Clinical Tool for Breast Cancer Management: Are We There Yet?, International Journal of Surgical Pathology, 17, 4, (285), (2009).
- JS Reis‐Filho and SR Lakhani, Breast cancer special types: why bother?, The Journal of Pathology, 216, 4, (394-398), (2008).
- E. Castro and E. de Alava, The risk of taking the part by the whole, Annals of Oncology, 19, 11, (1975), (2008).
- J S Reis‐Filho and A N J Tutt, Triple negative tumours: a critical review, Histopathology, 52, 1, (108-118), (2007).
- E A Rakha, M E El‐Sayed, J S Reis‐Filho and I O Ellis, Expression profiling technology: its contribution to our understanding of breast cancer, Histopathology, 52, 1, (67-81), (2007).
- Kai-Keen Shiu, David SP Tan and Jorge S Reis-Filho, Development of therapeutic approaches to ‘triple negative’ phenotype breast cancer, Expert Opinion on Therapeutic Targets, 12, 9, (1123), (2008).
- Tarek M. A. Abdel-Fatah, Desmond G. Powe, Zsolt Hodi, Jorge S. Reis-Filho, Andrew H. S. Lee and Ian O. Ellis, Morphologic and Molecular Evolutionary Pathways of Low Nuclear Grade Invasive Breast Cancers and Their Putative Precursor Lesions: Further Evidence to Support the Concept of Low Nuclear Grade Breast Neoplasia Family, The American Journal of Surgical Pathology, 32, 4, (513), (2008).
- Aleata A. Triplett, Cristina Montagna and Kay-Uwe Wagner, A Mammary-Specific, Long-range Deletion on Mouse Chromosome 11 Accelerates Brca1-Associated Mammary Tumorigenesis, Neoplasia, 10, 12, (1325), (2008).
- R. Shakya, M. Szabolcs, E. McCarthy, E. Ospina, K. Basso, S. Nandula, V. Murty, R. Baer and T. Ludwig, The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression, Proceedings of the National Academy of Sciences, 105, 19, (7040), (2008).
- Fernanda Milanezi, Silvia Carvalho and Fernando C Schmitt, EGFR/HER2 in breast cancer: a biological approach for molecular diagnosis and therapy, Expert Review of Molecular Diagnostics, 10.1586/14737159.8.4.417, 8, 4, (417-434), (2014).
- Patrick E. Corsino, Bradley J. Davis, Peter H. Nörgaard, Nicole N Teoh Parker, Mary Law, William Dunn and Brian K. Law, Mammary Tumors Initiated by Constitutive Cdk2 Activation Contain an Invasive Basal-like Component, Neoplasia, 10, 11, (1240), (2008).
- Emad A. Rakha, Jorge S. Reis-Filho and Ian O. Ellis, Basal-Like Breast Cancer: A Critical Review, Journal of Clinical Oncology, 26, 15, (2568), (2008).
- Matthew J. Smalley, Jorge S. Reis-Filho and Alan Ashworth, BRCA1 and stem cells: tumour typecasting, Nature Cell Biology, 10, 4, (377), (2008).
- Leslie K. Diaz, Vincent L. Cryns, W. Fraser Symmans and Nour Sneige, Triple Negative Breast Carcinoma and the Basal Phenotype: From Expression Profiling to Clinical Practice, Advances in Anatomic Pathology, 14, 6, (419), (2007).
- Joana Paredes, Ana Luísa Correia, Ana Sofia Ribeiro, André Albergaria, Fernanda Milanezi and Fernando C Schmitt, P-cadherin expression in breast cancer: a review, Breast Cancer Research, 9, 5, (2007).
- Jennifer R. Choo and Torsten O. Nielsen, Biomarkers for Basal-like Breast Cancer, Cancers, 10.3390/cancers2021040, 2, 2, (1040-1065), (2010).
