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

Zinab O. Doha, Xiaoyan Wang, Nicholas L. Calistri, Jennifer Eng, Colin J. Daniel, Luke Ternes, Eun Na Kim, Carl Pelz, Michael Munks, Courtney Betts, Sunjong Kwon, Elmar Bucher, Xi Li, Trent Waugh, Zuzana Tatarova, Dylan Blumberg, Aaron Ko, Nell Kirchberger, Jennifer A. Pietenpol, Melinda E. Sanders, Ellen M. Langer, Mu-Shui Dai, Gordon Mills, Koei Chin, Young Hwan Chang, Lisa M. Coussens, Joe W. Gray, Laura M. Heiser and Rosalie C. Sears ()
Additional contact information
Zinab O. Doha: Oregon Health & Science University
Xiaoyan Wang: Oregon Health & Science University
Nicholas L. Calistri: Oregon Health & Science University
Jennifer Eng: Oregon Health & Science University
Colin J. Daniel: Oregon Health & Science University
Luke Ternes: Oregon Health & Science University
Eun Na Kim: Oregon Health & Science University
Carl Pelz: Oregon Health & Science University
Michael Munks: Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University
Courtney Betts: Oregon Health and Science University
Sunjong Kwon: Oregon Health & Science University
Elmar Bucher: Oregon Health & Science University
Xi Li: Division of Oncologic Sciences, Oregon Health and Science University
Trent Waugh: Oregon Health & Science University
Zuzana Tatarova: Oregon Health & Science University
Dylan Blumberg: Oregon Health & Science University
Aaron Ko: Oregon Health and Science University
Nell Kirchberger: Oregon Health and Science University
Jennifer A. Pietenpol: Vanderbilt University Medical Center
Melinda E. Sanders: Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center
Ellen M. Langer: Oregon Health & Science University
Mu-Shui Dai: Oregon Health & Science University
Gordon Mills: Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University
Koei Chin: Oregon Health & Science University
Young Hwan Chang: Oregon Health & Science University
Lisa M. Coussens: Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University
Joe W. Gray: Oregon Health & Science University
Laura M. Heiser: Oregon Health & Science University
Rosalie C. Sears: Oregon Health & Science University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40841-6

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