<i>ESR1</i> mutations in breast cancer

Dustin, Derek; Gu, Guowei; Fuqua, Suzanne A.W.

doi:10.1002/cncr.32345

Cited by 194 publications

(149 citation statements)

References 82 publications

(188 reference statements)

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“…PDX tumors were treated when reached 200-300 mm 3 . Tumor size and animal weight were recorded twice weekly.…”

Section: Methodsmentioning

confidence: 99%

“…90-day slow release estrogen pellets were implanted subcutaneously into mice two days before cell injection (0.72 mg, Innovative Research of America). Positive tumor growth was assessed by determining the mice bearing a tumor greater than 75 mm 3…”

Section: B)mentioning

confidence: 99%

“…MAPK, PI3K/AKT) induced by receptor tyrosine kinase activity (e.g. EGFR, ERBB2) or by overexpression of substrates for cyclin-dependent kinases (CDKs) (3,4).…”

Section: Introductionmentioning

confidence: 99%

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Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

Simões

Santiago-Gómez

Chiodo

et al. 2020

Preprint

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PURPOSE:Estrogen receptor (ER) positive breast cancer is frequently sensitive to endocrine therapy. Multiple mechanisms of endocrine therapy resistance have been identified, including cancer stem-like cell (CSC) activity. Sulforaphane (SFN) has previously been shown to target CSCs but its mechanism of action is unclear. Here we investigate SFX-01, a stabilised formulation of SFN, for its effects on breast CSC activity in ER+ preclinical models and to study its mechanism. EXPERIMENTAL DESIGN: CSC activity was measured by mammosphere formation efficiency (MFE), aldehyde dehydrogenase (ALDH) activity, and tumor formation using patient samples and patient-derived xenograft (PDX) tumors treated with SFX-01 alone or in combination with tamoxifen or fulvestrant. Gene expression and SFN target proteins in treated samples were assessed. RESULTS: SFX-01 reduced MFE of both ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and ALDH activity of PDX tumors, which was reversed by combination with SFX-01. SFX-01 significantly reduced tumor initiating cell frequency in secondary transplants at limiting dilution and reduced the formation of spontaneous lung micrometastases by PDX tumors in mice. Mechanistically, we establish that both tamoxifen and fulvestrant induce STAT3 phosphorylation. SFX-01 suppressed phospho-STAT3 and SFN directly bound STAT3 in patient and PDX samples. Analysis of ALDH+ cells from endocrineresistant patient samples revealed activation of STAT3 target genes MUC1 and OSMR, which were inhibited by SFX-01 in patient samples. Increased expression of these genes after 3 months' endocrine treatment of ER+ patients (n=68) predicted poor prognosis. CONCLUSIONS:Our data establish the importance of STAT3 signaling in CSCmediated resistance to endocrine therapy and the potential of SFX-01 for improving clinical outcomes in ER+ breast cancer.

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“…PDX tumors were treated when reached 200-300 mm 3 . Tumor size and animal weight were recorded twice weekly.…”

Section: Methodsmentioning

confidence: 99%

Section: B)mentioning

confidence: 99%

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Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

Simões

Santiago-Gómez

Chiodo

et al. 2020

Preprint

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“…Pre-menopausal patients who still produce estrogen in the ovaries have traditionally been treated by surgically removing the ovaries though endocrine therapy has decreased this practice in recent years [511][512][513][514]. Resistant mutations arising from endocrine therapy treatment have been thoroughly reviewed recently [515,516]. Generally, activating mutations in ESR1 renders the receptor resistant to endocrine therapy [517].…”

Section: Classificationmentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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“…Der Nachweis einer ESR1-Mutation beim metastasierten HRpositiven Mammakarzinom kann mit einer Resistenz gegenüber Aromatase-Inhibitoren assoziiert sein. Diese Erkenntnis kann dann zu einem Einsatz von Fulvestrant führen [15].…”

Section: Ausblickunclassified

Was ist neu bei der Diagnostik und Therapie des Mammakarzinoms? – Aktuelle Standards in der Behandlung von Brustkrebs

Albert¹,

Stüber²,

Bauer³

et al. 2020

Dtsch Med Wochenschr

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Was ist neu? Vorsorge, Früherkennung und familiärer Brustkrebs Mit dem Mammografie-Screening für Frauen ab dem 50. Lebensjahr steht in Deutschland eine etablierte Früherkennungsmaßnahme zur Verfügung. Eine Reduktion der Mortalität ist gesichert. Das Screening kann mittlerweile auch bei Frauen über 70 fortgeführt werden. Durch intensive Forschung im Bereich des familiären Mammakarzinoms kann das Hochrisikopatientenkollektiv präziser bestimmt und einer intensivierten Früherkennung zugeführt werden. Therapie lokal begrenzter Stadien – Senkung der Radikalität Die Behandlung erfolgt zielgerichtet und so wenig radikal wie möglich. Nach neoadjuvanter Chemotherapie kann immer öfter auf eine Brustamputation verzichtet werden. Die axilläre Lymphknotendissektion (ALND) bleibt wenigen Fällen vorbehalten. Die molekulare Subtypisierung ermöglicht individualisierte medikamentöse Therapien in der kurativen Absicht. Rekonstruktive Chirurgie Das BIA-ALCL stellt eine seltene Brustimplantat-assoziierte Erkrankung dar, bei der in den meisten Fällen eine Heilung möglich ist. Trotz steigender Inzidenz ist von Implantateinlagen nach adäquater Aufklärung der Patientin in Deutschland nicht abzuraten. Therapie des metastasierten Karzinoms Zur Behandlung des metastasierten Mammakarzinoms sollte wenn möglich eine gut verträgliche Therapie zur Erhaltung der Lebensqualität gewählt werden. Auch hier stehen immer mehr individualisierte Optionen zur Verfügung. Nachsorge Der Zeitraum der Nachsorge weitet sich aufgrund der Tumorbiologie auf 10 Jahre aus. Ausblick Eine ESR1-Mutation kann zukünftig möglicherweise als prädiktiver Marker hinsichtlich einer antihormonellen Therapie in der Metastasierung genutzt werden. Für eine PD-1-Blockade gibt es vielversprechende Ergebnisse in der neoadjuvanten Behandlung des triple-negativen Mammakarzinoms (TNBC).

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ESR1 mutations in breast cancer

Cited by 194 publications

References 82 publications

Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Was ist neu bei der Diagnostik und Therapie des Mammakarzinoms? – Aktuelle Standards in der Behandlung von Brustkrebs

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