Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer
AuthorsSimões, Bruno M.; orcid: 0000-0003-1253-6657; email: firstname.lastname@example.org
Conole, Daniel; orcid: 0000-0002-3389-8377
Sims, Andrew H.; orcid: 0000-0001-9082-3665
Tate, Edward W.; orcid: 0000-0003-2213-5814
Howell, Sacha J.; orcid: 0000-0001-8141-6515; email: email@example.com
Clarke, Robert B.; orcid: 0000-0001-5407-3123; email: firstname.lastname@example.org
MetadataShow full item record
AbstractAbstract: 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.
CitationOncogene, volume 39, issue 25, page 4896-4908
PublisherNature Publishing Group UK
DescriptionFrom Springer Nature via Jisc Publications Router
History: received 2020-02-21, rev-recd 2020-05-13, accepted 2020-05-15, registration 2020-05-16, pub-electronic 2020-05-30, online 2020-05-30, pub-print 2020-06-18
Publication status: Published
Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272; Grant(s): IS-BRC-1215-20007, IS-BRC-1215-20007, IS-BRC-1215-20007
Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913; Grant(s): MAN-Q2
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs); doi: https://doi.org/10.13039/501100000849; Grant(s): NC/T001267/1
Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265; Grant(s): MR/K501311/1
Showing items related by title, author, creator and subject.
No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database StudyDominguez-Valentin, Mev; orcid: 0000-0001-7856-0057; email: Mev.Dominguez.Valentin@rr-research.no; Plazzer, John-Paul; orcid: 0000-0001-5114-4301; email: email@example.com; Sampson, Julian R.; email: Sampson@cardiff.ac.uk; Engel, Christoph; orcid: 0000-0002-7247-282X; email: firstname.lastname@example.org; Aretz, Stefan; orcid: 0000-0002-5228-1890; email: email@example.com; Jenkins, Mark A.; email: firstname.lastname@example.org; Sunde, Lone; email: email@example.com; Bernstein, Inge; email: firstname.lastname@example.org; Capella, Gabriel; orcid: 0000-0002-4669-7320; email: email@example.com; Balaguer, Francesc; orcid: 0000-0002-0206-0539; email: firstname.lastname@example.org; et al. (MDPI, 2021-06-28)Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.
Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.Eales, James M; orcid: 0000-0001-6238-5952; Jiang, Xiao; orcid: 0000-0002-1442-8927; Xu, Xiaoguang; orcid: 0000-0003-4568-1623; Saluja, Sushant; Akbarov, Artur; Cano-Gamez, Eddie; McNulty, Michelle T; Finan, Christopher; orcid: 0000-0002-3319-1937; Guo, Hui; orcid: 0000-0003-0282-6933; Wystrychowski, Wojciech; et al. (2021-05-06)The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?Park, JooYong; email: email@example.com; Choi, Ji-Yeob; email: firstname.lastname@example.org; Choi, Jaesung; email: email@example.com; Chung, Seokang; email: firstname.lastname@example.org; Song, Nan; orcid: 0000-0002-9182-1060; email: email@example.com; Park, Sue K.; orcid: 0000-0001-5002-9707; email: firstname.lastname@example.org; Han, Wonshik; email: email@example.com; Noh, Dong-Young; email: firstname.lastname@example.org; Ahn, Sei-Hyun; email: email@example.com; Lee, Jong Won; email: firstname.lastname@example.org; et al. (MDPI, 2021-05-14)In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.