TP53 mutation status can determine the function of estrogen receptor-beta (ESR2) in patients with triple-negative breast cancer (TNBC), according to new research. The results offer a potentially new way to stratify patients with TNBC for therapeutic interventions.
“The role of ESR2 in breast cancer has been elusive,” wrote study authors led by Gokul M. Das, PhD, of the Roswell Park Comprehensive Cancer Center in Buffalo, New York. Previous research has found both proliferative and anti-proliferative roles for ESR2, and the authors hypothesized that it may have bi-faceted functions depending on the cellular context. They analyzed whether the interaction between ESR2 and TP53 signaling might play a role in determining ESR2’s role, and how that might impact clinical outcomes in patients with TNBC.
They conducted this analysis using two patient cohorts, one from the Roswell Park Cancer Center (46 patients) and one from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; 308 patients). The results were published in the Journal of the National Cancer Institute.
They found that ESR2 binds directly to both wild-type and mutant TP53. This interaction, though, appeared to have opposite effects: ESR2 binding to wild-type TP53 resulted in a pro-proliferative state, while binding to mutant TP53 resulted in anti-proliferative effects. In cells expressing wild-type TP53, an experiment where ESR2 was silenced led to increased apoptosis; in contrast, increasing expression of ESR2 in those cells led to an increase in cell proliferation. The opposite effect was seen in cells with mutant TP53.
The researchers next showed that treatment with tamoxifen, an inhibitor of ESR1/ER-alpha, led to increased interaction between ESR2 and mutant TP53. The result of that interaction was to decrease those between mutant TP53 and TP73, which in turn increased rates of cell death.
To examine how these findings relate to clinical experience, they then examined the impact of TP53 status on the prognostic role of ESR2 in the METABRIC cohort; of the 308 patients, 259 had basal-like tumors and mutant TP53. In that group, low levels of ESR2 mRNA were associated with a poor prognosis in terms of breast cancer–specific survival (P = .001) and overall survival (P < .001). In contrast, in patients with wild-type TP53 (49 patients), lower levels of ESR2 mRNA were not associated with a difference in prognosis.
“Our data that treatment with tamoxifen can lead to sequestration of mutant TP53 away from TP73 and thereby reactivate tumor suppressor activities of TP73, provide for the first time, a strong rationale for suggesting that tamoxifen therapy could be beneficial to basal-type/TNBC patients expressing mutant TP53,” the authors concluded.
In an accompanying editorial, Sunil Badve, MBBS, and Yesim Gokmen-Polar, PhD, of the Indiana University School of Medicine in Indianapolis, wrote that the study has broader implications. “It documents the important principle of ‘company matters’ in understanding the impact of markers and mutations in cancers, including breast cancer,” they wrote. “The intracellular environment is a complex milieu wherein changes in one player can have a dramatic impact on DNA, RNA, and protein interactions. The players in the neighborhood could further affect cellular phenotype.”