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

Area of Science:

• Oncology
• Genetics
• Translational Research

Background:

• Triple-negative breast cancer (TNBC) presents significant challenges due to poor prognosis and limited therapeutic options.
• Existing mouse models often fail to capture the full complexity of human TNBC.
• There is a critical need for advanced preclinical models to study TNBC heterogeneity and develop novel treatments.

Purpose of the Study:

• To develop and characterize a novel murine model of triple-negative breast cancer (TNBC).
• To mimic common co-occurring mutations in human TNBC: MYC oncogene amplification and PTEN tumor suppressor deletion.
• To provide a preclinical platform for evaluating TNBC biology and therapeutic responses.

Main Methods:

• Creation of a genetically engineered mouse model (Myc;Ptenfl) by combining MYC amplification and PTEN deletion.
• Comprehensive molecular and spatial analyses including bulk and single-cell RNA sequencing.
• Multiplex tissue imaging to assess tumor heterogeneity and microenvironment.

Main Results:

• The Myc;Ptenfl model spontaneously develops heterogeneous triple-negative mammary tumors.
• These tumors exhibit histological and molecular features characteristic of human TNBC.
• The model demonstrates differential survival and therapeutic responses mirroring human TNBC inter- and intra-tumoral heterogeneity.

Conclusions:

• The Myc;Ptenfl mouse model accurately recapitulates key aspects of human TNBC, including its heterogeneity.
• This model serves as a valuable preclinical tool for investigating TNBC biology.
• It facilitates the assessment of drug responses across the spectrum of patient TNBC characteristics.