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

ABSTRACTPURPOSEEstrogen 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 DESIGNCSC 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.RESULTSSFX-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 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.CONCLUSIONSOur 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.

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Abstract 5544: Patient-derived xenograft study reveals the pharmacology and the role of ESR1 gene aberrations in endocrine therapy resistance of ER positive breast cancer

10.1158/1538-7445.am2014-5544 ◽

2014 ◽

Cited By ~ 1

Author(s):

Triparna Sen ◽

Shunqiang Li ◽

Jieya Shao ◽

Robert Crowder ◽

Robert Kitchens ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Therapy Resistance ◽

Endocrine Therapy Resistance ◽

Patient Derived Xenograft ◽

Esr1 Gene ◽

Er Positive ◽

Positive Breast Cancer

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Endocrine therapy resistance in estrogen receptor (ER)-positive breast cancer

Drug Discovery Today ◽

10.1016/j.drudis.2016.05.012 ◽

2016 ◽

Vol 21 (7) ◽

pp. 1181-1188 ◽

Cited By ~ 33

Author(s):

Tommaso De Marchi ◽

John A. Foekens ◽

Arzu Umar ◽

John W.M. Martens

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Endocrine Therapy ◽

Therapy Resistance ◽

Endocrine Therapy Resistance ◽

Er Positive ◽

Positive Breast Cancer

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Aberrant Regulation of RAD51 Promotes Resistance of Neoadjuvant Endocrine Therapy in ER-positive Breast Cancer

Scientific Reports ◽

10.1038/s41598-019-49373-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Yan Jia ◽

Yueshuai Song ◽

Guolei Dong ◽

Chunfang Hao ◽

Weipeng Zhao ◽

...

Keyword(s):

Breast Cancer ◽

Aromatase Inhibitor ◽

Endocrine Therapy ◽

Functional Enrichment ◽

Endocrine Treatment ◽

Main Function ◽

Neoadjuvant Endocrine Therapy ◽

Severe Problem ◽

Er Positive ◽

Positive Breast Cancer

Abstract Breast cancer is one of the most common malignant cancers affecting females. Estrogen receptor (ER)-positive breast cancer is responsive to endocrine therapy. Although current therapies offer favorable prospects for improving survival, the development of resistance remains a severe problem. In this study, we explored the resistance mechanisms of ER-positive breast cancer to neoadjuvant endocrine therapy. Microarray data of GSE87411 contained 109 pairs of samples from Z1031 trial, including untreated samples and post-treated samples with neoadjuvant aromatase inhibitor (AI) therapy. The differentially expressed genes (DEGs) were obtained from two different comparisons: untreated samples versus post-treated samples with AIs, and post-treated samples sensitive versus resistant to AIs. Multiple bioinformatic methods were applied to evaluate biological function, protein-protein network and potential binding between target protein and aromatase inhibitor. Then, regulation of gene expression, DNA methylation and clinicopathological factors of breast cancer were further analyzed with TCGA data. From GSE87411 dataset, 30 overlapped DEGs were identified. Cell division was found to be the main function of overlapped DEGs by functional enrichment and gene ontology (GO) analysis. RAD51 recombinase (RAD51), a key protein of homologous recombination, was detected to interact with BReast CAncer genes 2 (BRCA2). Moreover, according to the docking simulation, RAD51 might potentially bind to AIs. Overexpressed RAD51 was associated with hypermethylation of BRCA2, resistance to AIs and poor overall survival of patients with ER-positive breast cancer. Furthermore, RAD51 was found to be a better indicator than MKI67 for predicting resistance in neoadjuvant setting. The results indicated that methylation of BRCA2 led to incomplete suppression on RAD51, which caused an increased expression of RAD51, subsequently AI-resistance and poor prognosis in ER-positive breast cancer. RAD51 could be a new candidate used as a predicative marker and therapeutic target in neoadjuvant endocrine treatment.

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Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽

10.3390/cancers13040771 ◽

2021 ◽

Vol 13 (4) ◽

pp. 771

Author(s):

Tessa A. M. Mulder ◽

Mirjam de With ◽

Marzia del Re ◽

Romano Danesi ◽

Ron H. J. Mathijssen ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Outcome ◽

Cancer Patients ◽

Plasma Concentrations ◽

Tamoxifen Treatment ◽

Current Status ◽

Endocrine Treatment ◽

Breast Cancer Patients ◽

Er Positive ◽

Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

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