ESR1 and p53 interactome alteration defines mechanisms of tamoxifen response in luminal breast cancer
Chetan C. Oturkar,
Spencer R. Rosario,
Alan D. Hutson,
Adrianne Groman,
Stephen B. Edge,
Carl D. Morrison,
Wendy M. Swetzig,
Jianmin Wang,
Jun Hyoung Park,
Benny Abraham Kaipparettu,
Prashant K. Singh,
Shicha Kumar,
Helen H. Cappuccino,
Manish Ranjan,
Araba Adjei,
Mohammad Ghasemi,
Andrew K.L. Goey,
Swati Kulkarni,
Gokul M. Das
Affiliations
Chetan C. Oturkar
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Spencer R. Rosario
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Alan D. Hutson
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Adrianne Groman
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Stephen B. Edge
Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Carl D. Morrison
Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Wendy M. Swetzig
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Jianmin Wang
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Jun Hyoung Park
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Benny Abraham Kaipparettu
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Prashant K. Singh
Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Shicha Kumar
Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Helen H. Cappuccino
Department of Breast Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Manish Ranjan
Division of Breast Surgery, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
Araba Adjei
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Mohammad Ghasemi
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Andrew K.L. Goey
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Swati Kulkarni
Division of Breast Surgery, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA; Corresponding author
Gokul M. Das
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; Corresponding author
Summary: The canonical mechanism behind tamoxifen’s therapeutic effect on estrogen receptor α/ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to tamoxifen (Tam) therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remains unclear. In a window-of-opportunity trial on patients with newly diagnosed stage I–III ESR1+/HER2/wild-type p53 breast cancer who were randomized to arms with or without Tam prior to surgery, we reveal that the ESR1-p53 interaction in tumors was inhibited by Tam. This resulted in functional reactivation of p53 leading to transcriptional reprogramming that favors tumor-suppressive signaling, as well as downregulation of oncogenic pathways. These findings illustrating the convergence of ESR1 and p53 signaling during Tam therapy enrich mechanistic understanding of the impact of p53 on the response to Tam therapy.
