Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer

Jonathan T. Lei, Jieya Shao, Jin Zhang, Michael Iglesia, Doug W. Chan, Jin Cao, Meenakshi Anurag, Purba Singh, Xiaping He, Yoshimasa Kosaka, Ryoichi Matsunuma, Robert Crowder, Jeremy Hoog, Chanpheng Phommaly, Rodrigo Goncalves, Susana Ramalho, Raquel Mary Rodrigues Peres, Nindo Punturi, Cheryl Schmidt, Alex BartramEric Jou, Vaishnavi Devarakonda, Kimberly R. Holloway, W. Victoria Lai, Oliver Hampton, Anna Rogers, Ethan Tobias, Poojan A. Parikh, Sherri R. Davies, Shunqiang Li, Cynthia X. Ma, Vera Jean Suman, Kelly K. Hunt, Mark A. Watson, Katherine A. Hoadley, E Aubrey Thompson, Xi Chen, Shyam M. Kavuri, Chad J. Creighton, Christopher A. Maher, Charles M. Perou, Svasti Haricharan, Matthew J. Ellis

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1–6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective. Lei et al. show that transcriptionally active estrogen receptor gene (ESR1) fusions identified from late-stage, treatment-refractory estrogen receptor-positive (ER+) breast cancer drive pan-endocrine therapy resistance and metastatic progression. Growth of breast tumors driven by ESR1 fusions at primary and metastatic sties can be suppressed with a CDK4/6 inhibitor.

Original languageEnglish (US)
Pages (from-to)1434-1444.e7
JournalCell Reports
Volume24
Issue number6
DOIs
StatePublished - Aug 7 2018

Fingerprint

Gene Fusion
Estrogen Receptors
Fusion reactions
Genes
Breast Neoplasms
Hordeolum
Estrogens
Growth
Neoplasm Metastasis
RNA Sequence Analysis
Therapeutics
Estrogen Receptor alpha
Heterografts
Disease Progression
Exons
Lung
Refractory materials
Tumors
RNA
Proteins

Keywords

  • breast cancer
  • EMT
  • endocrine therapy resistance
  • ESR1 fusions
  • metastasis
  • PDX

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lei, J. T., Shao, J., Zhang, J., Iglesia, M., Chan, D. W., Cao, J., ... Ellis, M. J. (2018). Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer. Cell Reports, 24(6), 1434-1444.e7. https://doi.org/10.1016/j.celrep.2018.07.009

Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer. / Lei, Jonathan T.; Shao, Jieya; Zhang, Jin; Iglesia, Michael; Chan, Doug W.; Cao, Jin; Anurag, Meenakshi; Singh, Purba; He, Xiaping; Kosaka, Yoshimasa; Matsunuma, Ryoichi; Crowder, Robert; Hoog, Jeremy; Phommaly, Chanpheng; Goncalves, Rodrigo; Ramalho, Susana; Peres, Raquel Mary Rodrigues; Punturi, Nindo; Schmidt, Cheryl; Bartram, Alex; Jou, Eric; Devarakonda, Vaishnavi; Holloway, Kimberly R.; Lai, W. Victoria; Hampton, Oliver; Rogers, Anna; Tobias, Ethan; Parikh, Poojan A.; Davies, Sherri R.; Li, Shunqiang; Ma, Cynthia X.; Suman, Vera Jean; Hunt, Kelly K.; Watson, Mark A.; Hoadley, Katherine A.; Thompson, E Aubrey; Chen, Xi; Kavuri, Shyam M.; Creighton, Chad J.; Maher, Christopher A.; Perou, Charles M.; Haricharan, Svasti; Ellis, Matthew J.

In: Cell Reports, Vol. 24, No. 6, 07.08.2018, p. 1434-1444.e7.

Research output: Contribution to journalArticle

Lei, JT, Shao, J, Zhang, J, Iglesia, M, Chan, DW, Cao, J, Anurag, M, Singh, P, He, X, Kosaka, Y, Matsunuma, R, Crowder, R, Hoog, J, Phommaly, C, Goncalves, R, Ramalho, S, Peres, RMR, Punturi, N, Schmidt, C, Bartram, A, Jou, E, Devarakonda, V, Holloway, KR, Lai, WV, Hampton, O, Rogers, A, Tobias, E, Parikh, PA, Davies, SR, Li, S, Ma, CX, Suman, VJ, Hunt, KK, Watson, MA, Hoadley, KA, Thompson, EA, Chen, X, Kavuri, SM, Creighton, CJ, Maher, CA, Perou, CM, Haricharan, S & Ellis, MJ 2018, 'Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer', Cell Reports, vol. 24, no. 6, pp. 1434-1444.e7. https://doi.org/10.1016/j.celrep.2018.07.009
Lei, Jonathan T. ; Shao, Jieya ; Zhang, Jin ; Iglesia, Michael ; Chan, Doug W. ; Cao, Jin ; Anurag, Meenakshi ; Singh, Purba ; He, Xiaping ; Kosaka, Yoshimasa ; Matsunuma, Ryoichi ; Crowder, Robert ; Hoog, Jeremy ; Phommaly, Chanpheng ; Goncalves, Rodrigo ; Ramalho, Susana ; Peres, Raquel Mary Rodrigues ; Punturi, Nindo ; Schmidt, Cheryl ; Bartram, Alex ; Jou, Eric ; Devarakonda, Vaishnavi ; Holloway, Kimberly R. ; Lai, W. Victoria ; Hampton, Oliver ; Rogers, Anna ; Tobias, Ethan ; Parikh, Poojan A. ; Davies, Sherri R. ; Li, Shunqiang ; Ma, Cynthia X. ; Suman, Vera Jean ; Hunt, Kelly K. ; Watson, Mark A. ; Hoadley, Katherine A. ; Thompson, E Aubrey ; Chen, Xi ; Kavuri, Shyam M. ; Creighton, Chad J. ; Maher, Christopher A. ; Perou, Charles M. ; Haricharan, Svasti ; Ellis, Matthew J. / Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer. In: Cell Reports. 2018 ; Vol. 24, No. 6. pp. 1434-1444.e7.
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abstract = "RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1–6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective. Lei et al. show that transcriptionally active estrogen receptor gene (ESR1) fusions identified from late-stage, treatment-refractory estrogen receptor-positive (ER+) breast cancer drive pan-endocrine therapy resistance and metastatic progression. Growth of breast tumors driven by ESR1 fusions at primary and metastatic sties can be suppressed with a CDK4/6 inhibitor.",
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AU - Cao, Jin

AU - Anurag, Meenakshi

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AU - Kosaka, Yoshimasa

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AU - Crowder, Robert

AU - Hoog, Jeremy

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AU - Goncalves, Rodrigo

AU - Ramalho, Susana

AU - Peres, Raquel Mary Rodrigues

AU - Punturi, Nindo

AU - Schmidt, Cheryl

AU - Bartram, Alex

AU - Jou, Eric

AU - Devarakonda, Vaishnavi

AU - Holloway, Kimberly R.

AU - Lai, W. Victoria

AU - Hampton, Oliver

AU - Rogers, Anna

AU - Tobias, Ethan

AU - Parikh, Poojan A.

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AU - Ma, Cynthia X.

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AU - Watson, Mark A.

AU - Hoadley, Katherine A.

AU - Thompson, E Aubrey

AU - Chen, Xi

AU - Kavuri, Shyam M.

AU - Creighton, Chad J.

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