08 May AACR25: New therapeutic strategy against triple negative breast cancer: Synergistic effect of tamoxifen and doxorubicin on a novel estrogen receptor

MedicalResearch.com Interview responses from:

Dr. Gokul Das

First author Gokul Das, PhD, Professor of Oncology and Co-Director of the Breast Translational Group, Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center

Chetan Oturkar, PhD, Research Assistant Professor in the Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, first author on the study

MedicalResearch.com: What is the background for this study? 

Dr. Gokul Das: Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer for which effective targeted therapies are not available, and which rapidly becomes resistant to chemotherapy. TNBC tumors are negative for estrogen receptor α (ERα), progesterone receptor (PR), and HER-2/neu receptor. Endocrine therapy or HER2-targeted therapies are not effective against TNBC. Currently available options including immunotherapy benefit only some patients. They are cost-prohibitive and have severe adverse effects. Therefore, there is an unmet need for rationally designed therapies for TNBC. Although ERα is absent in TNBC, majority of these tumors express estrogen receptor beta (ERβ), a structurally related but functionally distinct isoform of the estrogen receptor coded by a different gene. Tumor suppressor protein p53 is mutated in the majority (80%) of TNBC. p53, when mutated, loses its tumor suppression capabilities, and instead gains oncogenic or tumor-driving functions.  One of the major oncogenic functions of mutant p53 is to bind and inactivate another tumor suppressor named p73.  The Das laboratory has been focusing on the mechanisms underlying the estrogen receptor β-p53-p73 axis for discovering rational and effective therapeutic strategies against TNBC.

MedicalResearch.com: What are the main findings? 

Dr. Chetan Oturkar: Studies from the Das laboratory have shown that ERβ binds to mutated p53 (mutant p53) and inhibits tumor-driving activities of mutant p53 by sequestering it away from p73. This results in the reactivation of p73 as a tumor suppressor, leading to death of tumor cells. Importantly, we showed that anti-hormone therapeutic agent tamoxifen enhances ERβ binding to mutant p53 leading to increased activation of p73 and tumor cell killing. This anti-tumor effect is further augmented when tamoxifen is combined with a widely used chemotherapeutic drug doxorubicin (Adriamycin). Tamoxifen increases the effect of doxorubicin indicating that when combined with tamoxifen, doses of doxorubicin lower than what is in current clinical practice can be used. This itself will be a huge advantage given the severe adverse effects of doxorubicin. The anti-tumor effects of the combination are more than the sum of the effects of individual drugs. In other words, these two drugs act synergistically.

Doxorubicin, along with other chemotherapeutic agents, has been used to treat TNBC patients. However, the tumors soon become resistant to this drug. Moreover, doxorubicin has serious adverse effects on the patient, including cardiac arrest upon continued usage. Tamoxifen has been used successfully to treat ERα-positive breast cancer, and has relatively low adverse effects; however, it has not been used for treatment of TNBC because TNBC lacks ERα, the conventional target of tamoxifen. Our studies have challenged this conventional paradigm by demonstrating that tamoxifen is effective in killing TNBC cells harboring mutant p53. Thus, we are repurposing tamoxifen to treat molecularly stratified TNBC based on the presence of mutant p53 and ERβ.

MedicalResearch.com:  Would these markers help guide prognosis or therapy? 

Dr. Gokul Das: ERβ and mutant 53 together will guide therapeutic stratification of TNBC to those that will be responsive to tamoxifen and doxorubicin combination therapy. 60-80% of TNBC will fall under this category.

MedicalResearch.com: What should readers take away from your report?

Dr. Gokul Das: While both tamoxifen and doxorubicin (Adriamycin) are FDA-approved and individually used for years for other diseases including certain types of breast cancer, our rationally designed novel combination represents a new approach to treatment of TNBC. Repurposing Tam, a commonly used, relatively well tolerated drug for a novel indication in TNBC will have huge impact. As majority of TNBCs express mutant p53 and ER beta, we believe a significant proportion of TNBC patients will be eligible for this therapeutic approach. A major advantage of our drug repurposing approach is that pharmacokinetic and toxicity profiles of tamoxifen and doxorubicin have been already established in previous clinical trials, and therefore, the drug development time can be substantially shortened. Our approach could be a more cost-effective way to treat TNBC in both the US and the world at large. This approach could lead to an impactive combination therapy that is fundamentally more beneficial in terms of cost (low financial toxicity), effectiveness, and safety (low physiological toxicity).

MedicalResearch.com:  What recommendations do you have for future research as a result of this study? 

Dr. Gokul Das: We recommend neo-adjuvant and adjuvant clinical trials with tamoxifen and doxorubicin combination therapy in TNBC patients.  This recommendation is also supported by one of our earlier published observations (not part of our current poster): Clinical proof-of-principle for this phenomenon came from a patient with metastatic ERβ and mutant p53-expressing TNBC who had significant tumor regression following treatment with tamoxifen (Case report in collaboration with Harvard/MGH oncologist Dr. Bardia and team: The Oncologist, 2023; 28, 358–363,

https://academic.oup.com/oncolo/article/28/4/358/7034511)

Furthermore, there is potential to combine tamoxifen with other therapeutic regimens as well.

No disclosures.

Citation:

AACR 2025 abstract LB005, “Synergistic effect of tamoxifen and doxorubicin on a novel estrogen receptorβ-p53-p73 axis: A new therapeutic strategy against triple negative breast cancer”

More information:

Leon-Ferre R, Jonas SF, Salgado R, et al. Tumor-infiltrating lymphocytes as a prognostic biomarker in early-stage triple-negative breast cancer. JAMA. 2024;331(15):1281-1290. doi:10.1001/jama.2024.2767

Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. New England Journal of Medicine. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215

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Last Updated on May 8, 2025 by Marie Benz MD FAAD