ESR1 and p53 Interactome Defines Mechanisms of Therapeutic Response to Tamoxifen Therapy in Luminal Breast Cancer Patients

The canonical mechanism behind tamoxifen (Tam)’s therapeutic effect on estrogen receptor  /ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to Tam therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remain 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 contribute to mechanistic understanding of the impact of p53 on the response to Tam therapy.