A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

Area of Science:

• Oncology
• Cancer Biology
• Molecular Medicine

Background:

• Epidermal growth factor receptor (EGFR) targeted therapies show unpredictable efficacy in breast cancer.
• Triple-negative breast cancer (TNBC) remains a challenging subtype with limited targeted treatment options.

Purpose of the Study:

• To investigate the role of EGFR heterogeneity in TNBC response to EGFR inhibition.
• To identify specific cellular subpopulations driving tumor growth and metastasis in TNBC.

Main Methods:

• Screening of triple-negative breast cancer patient-derived xenografts (PDXs) for response to gefitinib.
• Single-cell RNA sequencing of exceptional responder xenografts.
• Functional assays including ALDH activity, sphere formation, and tumorigenicity/metastasis assays.
• Analysis of EGFR expression in sorted subpopulations.

Main Results:

• A subset of TNBC PDXs responded to EGFR inhibition with gefitinib, correlating with heterogeneous wild-type EGFR expression.
• Single-cell analysis revealed EGFR-high (EGFR^hi) subpopulations with stem-like features, including enhanced tumorigenic and metastatic potential.
• EGFR^hi cells demonstrated self-renewal and hierarchical state transitions, generating both EGFR^hi and EGFR^lo cells.
• Similar tumorigenic EGFR^hi subpopulations were found in independent PDXs, reinforcing the correlation between EGFR heterogeneity and gefitinib sensitivity.

Conclusions:

• EGFR expression heterogeneity defines a subset of TNBC with stem-like properties and therapeutic vulnerabilities.
• An EGFR-dependent hierarchy exists in TNBC, with EGFR^hi cells driving tumor expansion and metastasis.
• These findings offer insights for patient stratification and targeted therapeutic interventions in TNBC.