MYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer

• Published in: Nature communications Vol. 14; no. 1; pp. 5665 - 21
• Main Authors: Doha, Zinab O., Wang, Xiaoyan, Calistri, Nicholas L., Eng, Jennifer, Daniel, Colin J., Ternes, Luke, Kim, Eun Na, Pelz, Carl, Munks, Michael, Betts, Courtney, Kwon, Sunjong, Bucher, Elmar, Li, Xi, Waugh, Trent, Tatarova, Zuzana, Blumberg, Dylan, Ko, Aaron, Kirchberger, Nell, Pietenpol, Jennifer A., Sanders, Melinda E., Langer, Ellen M., Dai, Mu-Shui, Mills, Gordon, Chin, Koei, Chang, Young Hwan, Coussens, Lisa M., Gray, Joe W., Heiser, Laura M., Sears, Rosalie C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.09.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/51; 45; 45/91; 49; 49/61; 631/67/1347; 631/67/70; 64; 64/60; 692/4028/67/1347; Aggression; Amplification; Animal models; Animals; Breast cancer; Complexity; Deregulation; Disease Models, Animal; Female; Gene deletion; Gene sequencing; Heterogeneity; Humanities and Social Sciences; Humans; Mammary Neoplasms, Animal; Medical prognosis; Mice; multidisciplinary; Mutation; Myc protein; Oncogenes; Patients; Proto-Oncogene Proteins c-myc - metabolism; PTEN Phosphohydrolase - genetics; PTEN protein; Science; Science (multidisciplinary); Spatial analysis; Triple Negative Breast Neoplasms - genetics; Tumor suppressor genes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40841-6

Triple-negative breast cancer (TNBC) patients have a poor prognosis and few treatment options. Mouse models of TNBC are important for development of new therapies, however, few mouse models represent the complexity of TNBC. Here, we develop a female TNBC murine model by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN . This Myc;Ptenfl model develops heterogeneous triple-negative mammary tumors that display histological and molecular features commonly found in human TNBC. Our research involves deep molecular and spatial analyses on Myc;Ptenfl tumors including bulk and single-cell RNA-sequencing, and multiplex tissue-imaging. Through comparison with human TNBC, we demonstrate that this genetic mouse model develops mammary tumors with differential survival and therapeutic responses that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC, providing a pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response. Few mouse models recapitulate the complexity of triple negative breast cancer (TNBC). Here, the authors develop and characterise a TNBC mouse model harbouring two common TNBC mutations: amplification of the oncogene MYC and deletion of the tumour suppressor PTEN.