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‘Important opportunity’ identified for tamoxifen in triple-negative breast cancer
TP53 status may explain the opposite functions of ER-beta in breast cancer cells, with the ER-beta and mutant TP53 combination predicting survival in triple-negative disease, according to study results published in Journal of the National Cancer Institute.
These findings suggest a potential role for tamoxifen in treating the notoriously aggressive tumors, according to researchers.
“Unlike other subtypes of breast cancers such as luminal breast cancer and HER2-enriched breast cancers, triple-negative breast cancers currently do not have effective therapies and therefore chemotherapy is the standard of care,” Gokul M. Das, PhD, associate professor of oncology in the department of pharmacology and therapeutics and co-director of the breast disease site research group at Roswell Park Comprehensive Cancer Center, said in an interview with HemOnc Today. “However, triple-negative breast cancers become resistant to chemotherapies very fast and the tumors progress aggressively. Therefore, there is urgent need to develop new therapeutic strategies against triple-negative breast cancer.”
Das and colleagues previously found that ER-alpha binds to p53 and blocks the ability of wild-type p53 to kill cancer cells in luminal breast cancer.
“Therefore, in this type of breast cancer, although p53 mutations are not very frequent,” he added. “Retrospective clinical studies by our group and others have shown that luminal breast cancers with normal p53 are more responsive to tamoxifen therapy.”
In the study, Das and colleagues evaluated ER-beta (ESR2) and TP53 interactions using multiple tests, including in situ proximity ligation assay. They assessed the transcriptional influences on TP53-target genes and cell proliferation in response to knocking down or overexpressing ESR2.
The researchers also used univariate Cox regression and log-rank tests to analyze patient survival by ESR2 expression levels and TP53 mutation status in a Basal-like/triple-negative breast cancer subgroup of two cohorts, METABRIC (n = 308) and Roswell (n = 46).
They found that ESR2 interaction with wild-type TP53 yielded pro-proliferative effects, whereas interaction with mutant TP53 produced antiproliferative effects. In cells expressing wild-type TP53, depleting ESR2 led to increased mean expression of TP53-target genes CDKN1A (control group, 1 vs. ESR2-depleted group, 2.08; P = .003) and BBC3 (control group, 1 vs. ESR2-depleted group, 1.92; P = .003).
However, in cells expressing mutant TP53, the researchers found reduced mean expression of CDKN1A (control group, 1 vs. ESR2-depleted group, 0.56; P = .02) and, to a statistically nonsignificant degree, of BBC3 (control group, 1 vs. ESR2-depleted group, 0.55). The opposite effects occurred when ESR2 was overexpressed.
ESR2-mutant TP53 interaction increased with tamoxifen, leading to reactivation of TP73 and cell death.
Mutant TP53-expressing Basal-like tumors with high levels of ESR2 expression appeared associated with better prognosis (METABRIC cohort: HR = 0.26; 95% CI, 0.08-0.84).
The researchers acknowledged limitations to the study, including a lack of sufficient Basal like/triple-negative breast cancer cases with wild-type TP53, and the unanticipated complexity of analyzing the role of ESR2 in ER-alpha-expressing or ER-positive tumors.
The study emphasizes the idea that “company matters” in understanding the influence of markers and mutations in cancer, according to a related editorial written by Sunil Badve, MBBS, FRCPath, the Joshua Edwards professor in pathology and laboratory medicine at Indiana University School of Medicine, and Yesim Gokmen-Polar, PhD, assistant research professor of pathology and laboratory medicine at Indiana University School of Medicine.
“The intracellular environment is a complex milieu wherein changes in one player can have a dramatic impact on DNA, RNA and protein interactions,” the editorial authors wrote. “The players in the neighborhood could further affect cellular phenotype. Acknowledging these processes also provides a reality check for those of us involved in precision medicine, wherein treatments are being prescribed based on the presence of single gene mutations. The cooperativity and interactions of cellular networks may, to a large extent, determine the prognostic and predictive utility of mutations in patients.”
Das said he and his team plan to further evaluate tamoxifen’s potential role in helping ER-beta to disable mutant p53.
“This approach is fundamentally better because tamoxifen is significantly less expensive, is one of the most tolerated anticancer agents and is one of the most studied drugs over decades,” he told HemOnc Today. “The therapeutic strategy has the potential to impact many patients with triple-negative breast cancer. Furthermore, given the exploding medical expense, our strategy will help health care in the U.S. and world at large.” – by Jennifer Byrne
For more information:
Gokul M. Das, PhD, can be reached at Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY 14263; email: gokul.das@roswellpark.org.
Disclosures: Das reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Badve and Gokmen-Polar report no relevant financial disclosures.