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, an interaction that may have therapeutic implications for triple-negative disease, a new study suggests.
Up to 80% of triple-negative breast cancers (TNBCs) express ESR2, but its role has been hard to pin down because of conflicting data, according to the investigators, who were led by senior author Gokul M. Das, PhD, of the department of pharmacology and therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Expression has been found to have both antiproliferative activity and proproliferative activity, depending on the experimental conditions.
Dr. Das and colleagues performed a series of in vitro assays in breast cancer cell lines and a clinical study of patients with basal-like TNBC from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (308 patients with TP53 mutational status determined by sequencing) and a Roswell cohort (46 patients with TP53 mutational status determined by immunohistochemistry).
Results showed that in vitro, ESR2 interaction with wild-type TP53 had proproliferative effects, whereas interaction of ESR2 with mutant TP53 had antiproliferative effects. The report is in the Journal of the National Cancer Institute.
In luminal breast cancer cell lines with wild-type TP53, compared with control, depleting ESR2 increased expression of the TP53 target genes CDKN1A and BBC3 (P = .003 and P = .003, respectively); in contrast, in those with mutant TP53, depleting ESR2 decreased their expression (P = .02 and P = .008). Opposite results were seen when ESR2 was instead overexpressed.
In cells with mutant TP53, tamoxifen treatment increased interaction of ESR2 with the mutant protein, ultimately leading to reactivation of TP73 and apoptosis.
Finally, among women with basal-like TNBC in the METABRIC cohort, high ESR2 expression was associated with better overall survival for those with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival for those with wild-type TP53 tumors (P = .05). Results were similar in the Roswell cohort.
“These findings suggest that ESR2-TP53 combination can be used to stratify TNBC into therapeutically actionable subgroups,” Dr. Das and coinvestigators proposed.
“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,” they concluded. “On the other hand, based on our data that ESR2 is proproliferative in the WT [wild-type] TP53 context, we predict that in TNBCs expressing WT TP53, tamoxifen or other agents that increase ESR2-WTP53 interaction may not only be ineffective as antitumor agents, but also may contribute to adverse outcome.”
The authors disclosed that they had no conflicts of interest. The study was supported by the several sources including the National Cancer Institute and Susan G. Komen for the Cure.
SOURCE: Mukhopadhyay UK et al. J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz051.
“The ability to selectively administer endocrine therapy should, in principle, lead to greater response rates,” according to an editorial by Sunil Badve, MBBS, FRCPath, and Yesim Gokmen-Polar, PhD (J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz052).
The study illustrates that “company matters” when it comes to the impact of markers and mutations in cancers, they maintain. “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.
“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 ... ” Dr. Badve and Dr. Gokmen-Polar noted. “The cooperativity and interactions of cellular networks may, to a large extent, determine the prognostic and predictive utility of mutations in patients.”
The new study “is a good step in this direction and provides compelling reasons to understand the combinatorial impact to determine clinically actionable strategies and solutions,” they concluded.
Dr. Badve and Dr. Gokmen-Polar are in the department of pathology and laboratory medicine at Indiana University, Indianapolis.
“The ability to selectively administer endocrine therapy should, in principle, lead to greater response rates,” according to an editorial by Sunil Badve, MBBS, FRCPath, and Yesim Gokmen-Polar, PhD (J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz052).
The study illustrates that “company matters” when it comes to the impact of markers and mutations in cancers, they maintain. “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.
“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 ... ” Dr. Badve and Dr. Gokmen-Polar noted. “The cooperativity and interactions of cellular networks may, to a large extent, determine the prognostic and predictive utility of mutations in patients.”
The new study “is a good step in this direction and provides compelling reasons to understand the combinatorial impact to determine clinically actionable strategies and solutions,” they concluded.
Dr. Badve and Dr. Gokmen-Polar are in the department of pathology and laboratory medicine at Indiana University, Indianapolis.
“The ability to selectively administer endocrine therapy should, in principle, lead to greater response rates,” according to an editorial by Sunil Badve, MBBS, FRCPath, and Yesim Gokmen-Polar, PhD (J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz052).
The study illustrates that “company matters” when it comes to the impact of markers and mutations in cancers, they maintain. “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.
“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 ... ” Dr. Badve and Dr. Gokmen-Polar noted. “The cooperativity and interactions of cellular networks may, to a large extent, determine the prognostic and predictive utility of mutations in patients.”
The new study “is a good step in this direction and provides compelling reasons to understand the combinatorial impact to determine clinically actionable strategies and solutions,” they concluded.
Dr. Badve and Dr. Gokmen-Polar are in the department of pathology and laboratory medicine at Indiana University, Indianapolis.
, an interaction that may have therapeutic implications for triple-negative disease, a new study suggests.
Up to 80% of triple-negative breast cancers (TNBCs) express ESR2, but its role has been hard to pin down because of conflicting data, according to the investigators, who were led by senior author Gokul M. Das, PhD, of the department of pharmacology and therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Expression has been found to have both antiproliferative activity and proproliferative activity, depending on the experimental conditions.
Dr. Das and colleagues performed a series of in vitro assays in breast cancer cell lines and a clinical study of patients with basal-like TNBC from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (308 patients with TP53 mutational status determined by sequencing) and a Roswell cohort (46 patients with TP53 mutational status determined by immunohistochemistry).
Results showed that in vitro, ESR2 interaction with wild-type TP53 had proproliferative effects, whereas interaction of ESR2 with mutant TP53 had antiproliferative effects. The report is in the Journal of the National Cancer Institute.
In luminal breast cancer cell lines with wild-type TP53, compared with control, depleting ESR2 increased expression of the TP53 target genes CDKN1A and BBC3 (P = .003 and P = .003, respectively); in contrast, in those with mutant TP53, depleting ESR2 decreased their expression (P = .02 and P = .008). Opposite results were seen when ESR2 was instead overexpressed.
In cells with mutant TP53, tamoxifen treatment increased interaction of ESR2 with the mutant protein, ultimately leading to reactivation of TP73 and apoptosis.
Finally, among women with basal-like TNBC in the METABRIC cohort, high ESR2 expression was associated with better overall survival for those with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival for those with wild-type TP53 tumors (P = .05). Results were similar in the Roswell cohort.
“These findings suggest that ESR2-TP53 combination can be used to stratify TNBC into therapeutically actionable subgroups,” Dr. Das and coinvestigators proposed.
“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,” they concluded. “On the other hand, based on our data that ESR2 is proproliferative in the WT [wild-type] TP53 context, we predict that in TNBCs expressing WT TP53, tamoxifen or other agents that increase ESR2-WTP53 interaction may not only be ineffective as antitumor agents, but also may contribute to adverse outcome.”
The authors disclosed that they had no conflicts of interest. The study was supported by the several sources including the National Cancer Institute and Susan G. Komen for the Cure.
SOURCE: Mukhopadhyay UK et al. J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz051.
, an interaction that may have therapeutic implications for triple-negative disease, a new study suggests.
Up to 80% of triple-negative breast cancers (TNBCs) express ESR2, but its role has been hard to pin down because of conflicting data, according to the investigators, who were led by senior author Gokul M. Das, PhD, of the department of pharmacology and therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. Expression has been found to have both antiproliferative activity and proproliferative activity, depending on the experimental conditions.
Dr. Das and colleagues performed a series of in vitro assays in breast cancer cell lines and a clinical study of patients with basal-like TNBC from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (308 patients with TP53 mutational status determined by sequencing) and a Roswell cohort (46 patients with TP53 mutational status determined by immunohistochemistry).
Results showed that in vitro, ESR2 interaction with wild-type TP53 had proproliferative effects, whereas interaction of ESR2 with mutant TP53 had antiproliferative effects. The report is in the Journal of the National Cancer Institute.
In luminal breast cancer cell lines with wild-type TP53, compared with control, depleting ESR2 increased expression of the TP53 target genes CDKN1A and BBC3 (P = .003 and P = .003, respectively); in contrast, in those with mutant TP53, depleting ESR2 decreased their expression (P = .02 and P = .008). Opposite results were seen when ESR2 was instead overexpressed.
In cells with mutant TP53, tamoxifen treatment increased interaction of ESR2 with the mutant protein, ultimately leading to reactivation of TP73 and apoptosis.
Finally, among women with basal-like TNBC in the METABRIC cohort, high ESR2 expression was associated with better overall survival for those with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival for those with wild-type TP53 tumors (P = .05). Results were similar in the Roswell cohort.
“These findings suggest that ESR2-TP53 combination can be used to stratify TNBC into therapeutically actionable subgroups,” Dr. Das and coinvestigators proposed.
“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,” they concluded. “On the other hand, based on our data that ESR2 is proproliferative in the WT [wild-type] TP53 context, we predict that in TNBCs expressing WT TP53, tamoxifen or other agents that increase ESR2-WTP53 interaction may not only be ineffective as antitumor agents, but also may contribute to adverse outcome.”
The authors disclosed that they had no conflicts of interest. The study was supported by the several sources including the National Cancer Institute and Susan G. Komen for the Cure.
SOURCE: Mukhopadhyay UK et al. J Natl Cancer Inst. 2019 Apr 16. doi: 10.1093/jnci/djz051.
FROM JOURNAL OF THE NATIONAL CANCER INSTITUTE
Key clinical point: In triple-negative breast cancer, TP53 mutational status influences the prognostic impact of estrogen receptor-beta (ESR2) expression.
Major finding: High ESR2 expression was associated with better overall survival among women with mutant TP53 tumors (hazard ratio for death, 0.26) but a trend toward poorer overall survival among women with wild-type TP53 tumors (P = .05).
Study details: In vitro study and retrospective cohort study of 354 women with basal-like triple-negative breast cancer.
Disclosures: The authors disclosed that they had no conflicts of interest. The study was supported by the several sources including the National Cancer Institute and Susan G. Komen for the Cure.
Source: Mukhopadhyay UK et al. J Natl Cancer Inst 2019 Apr 16 doi: 10.1093/jnci/djz051.