Amphiregulin retains ERα expression in acquired aromatase inhibitor resistant breast cancer cells
Yuanzhong Wang1, Yen-Dun Tony Tzeng1,2, Gregory Chang1
1Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, California, USA.
Abstract:
Acquired resistance to aromatase inhibitors (AIs) is a significant clinical issue in endocrine therapy for estrogen receptor (ER) positive breast cancer which accounts for the majority of breast cancer. Despite estrogen production being suppressed, ERα signaling remains active and plays a key role in most AI-resistant breast tumors. Here, we found that amphiregulin (AREG), an ERα transcriptional target and EGF receptor (EGFR) ligand, is crucial for maintaining ERα expression and signaling in acquired AI-resistant breast cancer cells. AREG was deregulated and critical for cell viability in ER+ AI-resistant breast cancer cells, and ectopic expression of AREG in hormone responsive breast cancer cells promoted endocrine resistance. RNA-sequencing and reverse phase protein array analyses revealed that AREG maintains ERα expression and signaling by activation of PI3K/Akt/mTOR signaling and upregulation of forkhead box M1 (FOXM1) and serum- and glucocorticoid-inducible kinase 3 (SGK3) expression. Our study uncovers a previously unappreciated role of AREG in maintaining ERα expression and signaling, and establishes the AREG-ERα crosstalk as a driver of acquired AI resistance in breast cancer.
Insights
Amphiregulin (AREG) maintains estrogen receptor (ER) signaling in acquired aromatase inhibitor (AI)-resistant breast cancer. This AREG-ER crosstalk drives endocrine resistance, offering new therapeutic targets.
Area of Science:
- Molecular Oncology
- Endocrinology
- Cancer Biology
Background:
- Acquired resistance to aromatase inhibitors (AIs) is a major challenge in treating estrogen receptor (ER)-positive breast cancer.
- Estrogen receptor alpha (ERα) signaling persists despite estrogen suppression in many AI-resistant tumors.
Purpose of the Study:
- To investigate the role of amphiregulin (AREG) in maintaining ERα signaling and driving acquired AI resistance in breast cancer.
- To elucidate the molecular mechanisms by which AREG contributes to endocrine resistance.
Main Methods:
- Analysis of AREG expression and function in ER-positive AI-resistant breast cancer cells.
- Ectopic expression of AREG in hormone-responsive breast cancer cells.
- RNA-sequencing and reverse phase protein array (RPPA) analyses.
Main Results:
- Amphiregulin (AREG) is upregulated and essential for the viability of ER-positive AI-resistant breast cancer cells.
- Ectopic AREG expression confers endocrine resistance in hormone-responsive breast cancer cells.
- AREG maintains ERα expression and signaling via PI3K/Akt/mTOR pathway activation and increased FOXM1 and SGK3 expression.
Conclusions:
- AREG plays a critical, previously unrecognized role in sustaining ERα expression and signaling in acquired AI resistance.
- The AREG-ERα crosstalk is identified as a key driver of acquired endocrine resistance in breast cancer, representing a potential therapeutic vulnerability.
