Tamoxifen and Doxorubicin Synergistically Target Estrogen Receptor β-Mutant p53-p73 Axis, a Therapeutically Actionable Vulnerability in Triple Negative Breast Cancer
Year: 2026
Type: preprint
Abstract: ABSTRACT Current therapeutic regimens for triple negative breast cancer (TNBC) are not very effective in majority of patients and have serious adverse effects. Tamoxifen (Tam), a selective estrogen receptor modulator (SERM), routinely used to treat estrogen receptor alpha (ERα)-positive breast cancer, has traditionally not been considered for TNBC therapy because it lacks expression of ERα, the canonical target of Tam. Challenging this conventional clinical paradigm, we have demonstrated, using genetic and pharmacological approaches, that Tam synergizes with DNA- damaging agent doxorubicin (Doxo) to increase cell death by both apoptosis and ferroptosis leading to growth inhibition of TNBC CDXs and PDXs expressing mutant p53. Mechanistically, these responses are dependent on ERβ-mutant p53 interaction enhanced by Tam, thereby disrupting p73-mutant p53 complex resulting in reactivation of p73 and transcriptomic reprogramming converging on apoptosis and ferroptosis. These studies demonstrate the potential for repurposing Tam with Doxo as an effective and safe therapeutic strategy to treat molecularly stratified TNBC. SIGNIFICANCE This study demonstrates synergy between Tam and Doxo in targeting a novel ERβ-mutant p53-p73 axis in TNBC to induce apoptosis, ferroptosis, and tumor regression. These results provide a mechanistic basis for repurposing Tam in combination with Doxo as an effective therapeutic strategy against TNBC, majority of which expresses mutant p53.
Authors: Chetan C Oturkar, Junhoung Park J, Iqbal Ijaz, Christina Adams, Utpal K Mukhopadhyay, Melissa Dolan, Alexander Caradori, Manasori Oshi, Yali Zhang, Jianmin Wang, Brent Boleslav, Donald Mager, Abhilash Nair, Tagari Samanta, Kwang Hwa Jung, Seung Yeop Han, Sukjin Yang, Abha Tiwari, Richa Mishra, John Ebos, Kazuaki Takabe, Kris Attwood, Benny A Kaipparettu, Gokul M Das
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1010591873, G1504377518, G2044051574, G3946254007, Patient-derived Xenograft and Advanced In Vivo Models (PDX-AIM) Core Facility of Texas, G4776147864, G518420523, G5566852224, P53 AND ESTROGEN IN PCNA EXPRESSION OSTEOSARCOMA CELLS, G7326920056, G7837447426, Role of Estrogen Receptor alpha-p53 Interaction in Resistance to Tamoxifen Therap, G9000180351, Roswell Park Cancer Center Support Grant, Functional Significance of individual p53 mutations in determining the role of estrogen receptor beta in triple negative breast cancer, Baylor College of Medicine Cancer Center - Cancer Center Support Grant, G931214414
OpenAlex ID: W7223287480