Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies

Gaillard, Stéphanie; Andreano, Kaitlyn J.; Steiner, M.; Jorgensen, Matthew S.; Davidson, Brittany; Havrilesky, Laura J.; Secord, Angeles Alvarez; Valea, Fidel A.; Colón‐Otero, Gerardo; Zajchowski, Deborah A.; Chang, Ching Yi; McDonnell, Donald P.; Berchuck, Andrew; Elvin, Julia A.

doi:10.1016/j.ygyno.2019.04.010

Cited by 29 publications

(37 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In breast cancer, activating mutations in ERα (mutESR1) frequently contribute to therapeutic resistance, especially to aromatase inhibitors. Although rare in untreated ovarian cancers—e.g., mutation rates of 3.5% in endometrioid and 0.3% in serous ovarian cancers [ 98 ]—their appearance after treatment may have important therapeutic consequences. In a case report of a patient with LGSOC who had a sustained response to anastrazole therapy for 5 years, the patient developed an isolated recurrent lesion that was found to contain an ESR1 -activating mutation (Y537S) [ 99 ].…”

Section: Use Of Estrogen-regulated Predictive Biomarkersmentioning

confidence: 99%

“…In a case report of a patient with LGSOC who had a sustained response to anastrazole therapy for 5 years, the patient developed an isolated recurrent lesion that was found to contain an ESR1 -activating mutation (Y537S) [ 99 ]. Further LGSOCs and some HGSOCs that have developed mutESR1 after treatment with aromatase inhibitors have now been identified, and these include the activating mutations of Y537S, Y537N and D538G [ 98 ] ( Figure 1 ). Since long-term therapy with aromatase inhibitors (AIs) may increase the frequency of these mutations, patients may need to be screened for their development.…”

Section: Use Of Estrogen-regulated Predictive Biomarkersmentioning

confidence: 99%

“…Since long-term therapy with aromatase inhibitors (AIs) may increase the frequency of these mutations, patients may need to be screened for their development. The presence of an activating mutation does not preclude the use of endocrine therapy; however, a switch to tamoxifen or fulvestrant treatment may be appropriate [ 98 ].…”

Section: Use Of Estrogen-regulated Predictive Biomarkersmentioning

confidence: 99%

See 2 more Smart Citations

Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer

Langdon

Herrington

Hollis

et al. 2020

Cancers

View full text Add to dashboard Cite

The estrogen receptor (ER) has functionality in selected ovarian cancer subtypes and represents a potential target for therapy. The majority (>80%) of high grade serous, low grade serous and endometrioid carcinomas and many granulosa cell tumors express ER-alpha (ERα), and these tumor types have demonstrated responses to endocrine therapy (tamoxifen and aromatase inhibitors) in multiple clinical studies. Biomarkers of responses to these drugs are actively being sought to help identify responsive cancers. Evidence for both pro-proliferative and pro-migratory roles for ERα has been obtained in model systems. ER-beta (ERβ) is generally considered to have a tumor suppressor role in ovarian cancer cells, being associated with the repression of cell growth and invasion. The differential expression of the specific ERβ isoforms may determine functionality within ovarian cancer cells. The more recently identified G protein-coupled receptor (GPER1; GPR30) has been shown to mediate both tumor-suppressive and tumor-promoting action in ovarian cancer cells, suggesting a more complex role. This review will summarize recent findings in this field.

show abstract

Section: Use Of Estrogen-regulated Predictive Biomarkersmentioning

confidence: 99%

Section: Use Of Estrogen-regulated Predictive Biomarkersmentioning

confidence: 99%

Section: Use Of Estrogen-regulated Predictive Biomarkersmentioning

confidence: 99%

See 1 more Smart Citation

Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer

Langdon

Herrington

Hollis

et al. 2020

Cancers

View full text Add to dashboard Cite

show abstract

“…In this study, we focused on the D538G mutation because it is the only specific alteration in the LBD; L536 and Y537 have been found to be mutated to several different amino acids (Gaillard et al 2019). In future studies, it will be interesting to determine if mutations to L536 and Y537 cause similar regulatory and phenotypic changes in endometrial cancer cells, because Y357S and D538G appear to cause mutation-specific alterations in breast cancer cells (Bahreini et al 2017;Jeselsohn et al 2018).…”

Section: A B C Dmentioning

confidence: 99%

Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer

et al. 2019

View full text Add to dashboard Cite

Estrogen receptor 1 (ESR1) mutations have been identified in hormone therapy-resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggest that mutant ESR1 exhibits estrogen-independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however, experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wild-type ESR1. The D538G mutation impacted expression, including a large set of nonestrogen-regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is distinct from constitutive ESR1 activity because mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, the D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.

show abstract

“…In this study, we focused on the D538G mutation because it is the only specific alteration in the LBD; L536 and Y537 have been found to be mutated to several different amino acids (Gaillard 2019). In future studies, it will be interesting to determine if mutations to L536 and Y537 cause similar regulatory and phenotypic changes in endometrial cancer cells, as Y357S and D538G appear to cause mutation specific alterations in breast cancer cells (Bahreini 2017;Jeselsohn 2018).…”

Section: Discussionmentioning

confidence: 99%

Estrogen-independent molecular actions of mutant estrogen receptor alpha in endometrial cancer

Blanchard

Vahrenkamp

Berrett

et al. 2018

Preprint

View full text Add to dashboard Cite

Estrogen receptor 1 (ESR1) mutations have been identified in hormone therapy resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggests that mutant ESR1 exhibits estrogen independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wildtype ESR1. The D538G mutation impacted expression, including a large set of non-estrogen regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is unique from constitutive ESR1 activity as mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.

show abstract

Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies

Cited by 29 publications

References 29 publications

Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer

Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer

Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer

Estrogen-independent molecular actions of mutant estrogen receptor alpha in endometrial cancer

Contact Info

Product

Resources

About