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

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. Here we investigate SFX-01, a stabilised formulation of sulforaphane (SFN), for its effects on breast CSC activity in ER+ preclinical models. SFX-01 reduced mammosphere formation efficiency (MFE) of ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and aldehyde dehydrogenase (ALDH) activity of patient-derived xenograft (PDX) tumors, which was reversed by combination with SFX-01. SFX-01 significantly reduced tumor-initiating cell frequency in secondary transplants 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 endocrine-resistant 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. Our data establish the importance of STAT3 signaling in CSC-mediated resistance to endocrine therapy and the potential of SFX-01 for improving clinical outcomes in ER+ breast cancer.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:39

Enthalten in:

Oncogene - 39(2020), 25 vom: 29. Juni, Seite 4896-4908

Sprache:

Englisch

Beteiligte Personen:

Simões, Bruno M [VerfasserIn]
Santiago-Gómez, Angélica [VerfasserIn]
Chiodo, Chiara [VerfasserIn]
Moreira, Tiago [VerfasserIn]
Conole, Daniel [VerfasserIn]
Lovell, Scott [VerfasserIn]
Alferez, Denis [VerfasserIn]
Eyre, Rachel [VerfasserIn]
Spence, Katherine [VerfasserIn]
Sarmiento-Castro, Aida [VerfasserIn]
Kohler, Bertram [VerfasserIn]
Morisset, Ludivine [VerfasserIn]
Lanzino, Marilena [VerfasserIn]
Andò, Sebastiano [VerfasserIn]
Marangoni, Elisabetta [VerfasserIn]
Sims, Andrew H [VerfasserIn]
Tate, Edward W [VerfasserIn]
Howell, Sacha J [VerfasserIn]
Clarke, Robert B [VerfasserIn]

Links:

Volltext

Themen:

Anticarcinogenic Agents
GA49J4310U
Isothiocyanates
Journal Article
Receptors, Estrogen
Research Support, Non-U.S. Gov't
STAT3 Transcription Factor
STAT3 protein, human
Sulforaphane
Sulfoxides

Anmerkungen:

Date Completed 07.12.2020

Date Revised 29.01.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1038/s41388-020-1335-z

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM310525519