A Novel Mouse Model that Recapitulates the Heterogeneity of Human Triple Negative Breast Cancer

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 targeted therapies, but few TNBC mouse models exist. Here, we developed a novel 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 murine model develops TN mammary tumors that display histological and molecular features commonly found in human TNBC. We performed deep omic analyses on Myc;Ptenfl tumors including machine learning for morphologic features, bulk and single-cell RNA-sequencing, multiplex immunohistochemistry and single-cell phenotyping. Through comparison with human TNBC, we demonstrated that this new genetic mouse model develops mammary tumors with differential survival that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC; providing a unique pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response.

Unraveling MYC’s Role in Orchestrating Tumor Intrinsic and Tumor Microenvironment Interactions Driving Tumorigenesis and Drug Resistance

“…Even though oncogenic MYC leads to the production of rapidly dividing cancer cells and an increase in genomic instability, one would expect these cells to be more vulnerable to DNA-damaging therapy. However, the opposite happens; high-MYC cancer cells exhibit prolonged survival even after DNA-damaging chemotherapy [ 21 , 23 , 186 ]. This evidence strongly indicates that oncogenic MYC in cancer cells triggers the development of a highly efficient DNA repair system, effectively countering the genomic damage induced by rapid proliferation, as well as chemotherapy and radiation therapy [ 89 ].…”

“…Thus, MYC cooperates with many other oncogenic or tumor suppressor genes to initiate tumorigenesis [ 3 ]. Its activation is also generally essential for tumorigenesis as shown in several animal models of cancer in which MYC alteration is required for tumor initiation, progression or maintenance [ 19 , 20 , 21 , 22 , 23 ]. Therefore, tumors with dysregulated MYC have been considered as “MYC-driven” and/or “MYC-addicted” tumors.…”

“…Moreover, high levels of MYC deregulation are associated with aggressive conditions and a poor prognosis. For example, in the triple-negative form of breast cancer (TNBC), the most aggressive subtype of breast cancer and the most difficult to treat, MYC is amplified in approximately 57% of cases in contrast to only 7–13% in luminal A-type (ER/PR-positive) cancers (a breast cancer subtype with a more favorable outcome) [ 23 , 29 ].…”

“…MYC plays a significant role in promoting the recruitment of immunosuppressive cells within the tumor microenvironment, including regulatory T cells (Treg) [ 23 , 55 , 103 , 116 , 117 ]. MYC in tumor cells influences Treg accumulation, activation and metabolic programming [ 118 ].…”