Paeoniflorin Enhances the Sensitivity of ER-Positive Breast Cancer Cells to Tamoxifen through Promoting Sirtuin 4

Tamoxifen is an effective drug for treating patients with advanced estrogen receptor-positive (ER+) breast cancer (BC), but not for all ER + BC patients. Drug tolerance is the biggest obstacle. In this study, we designed an experiment to investigate whether paeoniflorin affects the ER + BC cell’s sensitivity to tamoxifen in the T47D and MCF-7 cell lines. Herein, we found that paeoniflorin inhibited cell proliferation without inducing apoptosis. However, it enhanced tamoxifen-induced apoptosis in both cell lines. Immunoblotting revealed that paeoniflorin significantly increased the already elevated Bax/Bcl2 protein expression ratio and the caspase 3 activity levels, both induced by tamoxifen. Paeoniflorin was also found to increase SIRT4 expression, and deletion of SIRT4 could significantly reverse the inhibition of cell proliferation induced by paeoniflorin and significantly decrease paeoniflorin-enhanced apoptosis induced by tamoxifen. Moreover, protein expression detection revealed that paeoniflorin enhanced the tamoxifen-induced inhibition of STAT3 activation. Besides, the deletion of SIRT4 could significantly increase STAT3 activation in the T47D and MCF-7 cells. In conclusion, paeoniflorin suppressed STAT3 activation to enhance the sensitivity of ER-positive breast cancer cells to tamoxifen through promoting SIRT4 expression.

Biomarkers of everolimus efficacy in breast cancer therapy

Objective Everolimus is an inhibitor of serine/ threonine kinase mTOR. The drug is approved for the treatment of metastatic ER positive, HER2 negative breast cancers and benefits a subset of patients with these breast cancers in combination with hormonal therapies. Despite extensive efforts, no additional predictive biomarkers to guide therapeutic decisions for everolimus have been introduced in clinical practice. Data sources This paper discusses predictive biomarkers for everolimus efficacy in breast cancer. A search of the medline and web of science databases was performed using the words “everolimus” and “biomarkers”. References of retrieved articles were manually scanned for additional relevant articles. Data Summary Everolimus benefits a subset of patients with metastatic ER positive, HER2 negative breast cancers in combination with hormonal therapies. Despite extensive efforts no additional predictive biomarkers to guide therapeutic decisions for everolimus therapy have been confirmed for use in clinical practice. However, promising biomarker leads for everolimus efficacy in breast cancer have been suggested and include expression of proteins in the mTOR pathway in ER positive, HER2 negative breast cancers. In HER2 positive cancers PIK3CA mutations, and PTEN expression loss are prognostic. Other clinical predictive biomarkers with more limited data include characteristics derived from whole genome sequencing, subsets of circulating leukocytes and changes in Standardized Uptake Values (SUV) of Positron Emission Tomography (PET) scans. Conclusions Putative predictive biomarkers for everolimus efficacy in breast cancer patients, both genomic and clinical, deserve further study and could lead to a better selection of responsive patients.

Overexpression of BQ323636.1 Modulated AR/IL-8/CXCR1 Axis to Confer Tamoxifen Resistance in ER-Positive Breast Cancer

NCOR2 is a co-repressor for estrogen receptor (ER) and androgen receptor (AR). Our group previously identified a novel splice variant of NCOR2, BQ323636.1 (BQ), that mediates tamoxifen resistance via interference of NCOR2 repression on ER. Luciferase reporter assay showed BQ overexpression could enhance the transcriptional activity of androgen response element (ARE). We proposed that BQ employs both AR and ER to confer tamoxifen resistance. Through in silico analysis, we identified interleukin-8 (IL-8) as the sole ERE and ARE containing gene responsiveness to ER and AR activation. We confirmed that BQ overexpression enhanced the expression of IL-8 in ER+ve breast cancer cells, and AR inhibition reduced IL-8 expression in the BQ overexpressing cell lines, suggesting that AR was involved in the modulation of IL-8 expression by BQ. Moreover, we demonstrated that IL-8 could activate both AKT and ERK1/2 via CXCR1 to confer tamoxifen resistance. Targeting CXCR1/2 by a small inhibitor repertaxin reversed tamoxifen resistance of BQ overexpressing breast cancer cells in vitro and in vivo. In conclusion, BQ overexpression in ER+ve breast cancer can enhance IL-8 mediated signaling to modulate tamoxifen resistance. Targeting IL-8 signaling is a promising approach to overcome tamoxifen resistance in ER+ve breast cancer.

Effects of neoadjuvant trastuzumab, pertuzumab and palbociclib on Ki67 in HER2 and ER-positive breast cancer

The crosstalk between estrogen and HER2 receptors and cell-cycle regulation sustains resistance to endocrine therapy of HER2- and hormone receptor-positive breast cancer. We earlier reported that women with HER2 and ER-positive breast cancer receiving neoadjuvant dual HER2-block and palbociclib in the NA-PHER2 trial had Ki67 decrease and 27% pathological complete responses (pCR). We extended NA-PHER2 to Cohort B using dual HER2-block and palbociclib without fulvestrant and report here Ki67 drops at week-2 (mean change −25.7), at surgery (after 16 weeks, mean change −9.5), high objective response (88.5%) and pCR (19.2%). In Cohort C [Ki67 > 20% and HER2low (IHC 1+/2+ without gene amplification)], women also received fulvestrant, had dramatic Ki67 drop at week 2 (−29.5) persisting at surgery (−19.3), and objective responses in 78.3%. In view of the favorable tolerability and of the efficacy-predictive value of Ki67 drop at week-2, the chemotherapy-free approach of NA-PHER2 deserves further investigation in HER2 and ER-positive breast cancer. The trial is registered with ClinicalTrials.gov, number NCT02530424.

Regulation of Bcl-2 Family Proteins in Estrogen Receptor-Positive Breast Cancer and Their Implications in Endocrine Therapy

Estrogen receptor (ER)-positive breast cancer accounts for around two-thirds of breast cancer occurrences, with endocrine therapy serving as first-line therapy in most cases. Targeting estrogen signaling pathways, which play a central role in regulating ER+ breast cell proliferation and survival, has proven to improve patient outcomes. However, despite the undeniable advantages of endocrine therapy, a subset of breast cancer patients develop acquired or intrinsic resistance to ER-targeting agents, limiting their efficacy. The activation of downstream ER signaling pathways upregulates pro-survival mechanisms that have been shown to influence the response of cells to endocrine therapy. The Bcl-2 family proteins play a central role in cell death regulation and have been shown to contribute to endocrine therapy resistance, supporting the survival of breast cancer cells and enhancing cell death evasion. Due to the overexpression of anti-apoptotic Bcl-2 proteins in ER-positive breast cancer, the role of these proteins as potential targets in hormone-responsive breast cancer is growing in interest. In particular, recent advances in the development of BH3 mimetics have enabled their evaluation in preclinical studies with ER+ breast cancer models, and BH3 mimetics have entered early ER+ breast cancer clinical trials. This review summarizes the molecular mechanisms underlying the regulation of Bcl-2 family proteins in ER+ breast cancer. Furthermore, an overview of recent advances in research regarding the efficacy of BH3 mimetics in ER+ breast cancer has been provided.

Loss of HAS2 Confers Acquired Antiestrogen Resistance By Upregulating Ezrin Expression In ER-Positive Breast Cancer

Background: Resistance to endocrine therapy is a major challenge for estrogen receptor-positive (ER+) breast cancer patients, but the underlying mechanisms remain unclear. Methods: Loss of hyaluronan synthase 2 (Has2) in adaptive resistant cells to tamoxifen and fulvestrant was observed by immunblotting assay. CRISPR/Cas9 technology was used to knock out Has2 in MCF7 cells to verify the effect of Has2 on the expression of ER and Ezrin and Akt and MAPK/ERK signaling routes. We utilized an Ezrin small-interfering RNA and Ezrin inhibitor to inhibit Ezrin expression for evaluating Has2 and ERα expression and the Akt/MAPK signaling cascade upon tamoxifen or fulvestrant treatment.Results: In this work, we showed that a Has2-loss state was acquired from adaptive resistance to tamoxifen and fulvestrant in luminal BrCas. Notably, the adapted loss of Has2 induced acquired resistance to antiestrogens in estrogen receptor (ER)-positive breast cancer cells through up-regulating the expression of Ezrin. Furthermore, we found that the loss of Has2 promoted while the consequent increase of Ezrin inhibited ERα expression/activity through the Akt and MAPK/ERK signaling routes, indicating an opposite effect on ERα expression during the development of antiestrogens-resistance. Inhibition of Ezrin reversed Has2 and ERα expression and the Akt/MAPK signaling cascade upon tamoxifen or fulvestrant, suggesting a Has2-Ezrin-ER negative-feedback loop in governing cellular sensitivity to tamoxifen or fulvestrant in luminal-like breast cancer cells. Finally, Knockdown or inhibition of Ezrin restored sensitivity to antiestrogens, implying that Ezrin could be a potential therapeutic target to tackle endocrine resistance. Conclusions: Taken together, our findings provide a direct relationship between ERα and Has2 implicated in resistance to endocrine therapy and a new insight into how ERα-signaling is regulated upon antiestrogens treatment, suggesting a novel therapeutic target for ER-positive breast cancer.

Knockdown of vps54 aggravates tamoxifen-induced cytotoxicity in fission yeast

Tamoxifen (TAM) is an anticancer drug used to treat estrogen receptor (ER)‒positive breast cancer. However, its ER-independent cytotoxic and antifungal activities have prompted debates on its mechanism of action. To achieve a better understanding of the ER-independent antifungal action mechanisms of TAM, we systematically identified TAM-sensitive genes through microarray screening of the heterozygous gene deletion library in fission yeast (Schizosaccharomyces pombe). Secondary confirmation was followed by a spotting assay, finally yielding 13 TAM-sensitive genes under the drug-induced haploinsufficient condition. For these 13 TAM-sensitive genes, we conducted a comparative analysis of their Gene Ontology (GO) ‘biological process’ terms identified from other genome-wide screenings of the budding yeast deletion library and the MCF7breast cancer cell line. Several TAM-sensitive genes overlapped between the yeast strains and MCF7 in GO terms including ‘cell cycle’ (cdc2, rik1, pas1, and leo1), ‘signaling’ (sck2, oga1, and cki3), and ‘vesicle-mediated transport’ (SPCC126.08c, vps54, sec72, and tvp15), suggesting their roles in the ER-independent cytotoxic effects of TAM. We recently reported that the cki3 gene with the ‘signaling’ GO term was related to the ER-independent antifungal action mechanisms of TAM in yeast. In this study, we report that haploinsufficiency of the essential vps54 gene, which encodes the GARP complex subunit, significantly aggravated TAM sensitivity and led to an enlarged vesicle structure in comparison with the SP286 control strain. These results strongly suggest that the vesicle-mediated transport process might be another action mechanism of the ER-independent antifungal or cytotoxic effects of TAM.

Studentvurderingar av forholdet mellom engelsk og lokale språk på fem nordiske universitet

Denne undersøkinga handlar om korleis studentar opplever og vurderer den språklege praksisen dei møter gjennom utdanningsløpet. Under­søkinga fokuserer på studentane sine opplevingar og vurderingar knytt til bruk og meistring av engelsk og dei lokale språka i undervisinga. Først skildrar eg språkpolitiske retningslinjer i dei nordiske landa, der parallell­språk har vore den føretrekte språkpolitikken i høgare utdanning. Så gjer eg ein tematisk analyse av studentkommentarar frå ei spørjeundersøking som blei gjennomført på fem universitet i tre av dei nordiske landa. Trass i at studentane i hovudsak er positive til å bruke både engelsk og dei lokale språka, etterspør dei meir fokus på handteringa av dei ulike språka gjennom utdanningsløpet. Studentkommentarane syner at det kan vere utfordrande å lukkast med parallellspråkpolitikken. Nokre vanskar som studentane fortel om, knyter dei til eigne utfordringar med å forstå og bruke andre språk enn førstespråket, medan andre vanskar vert knytt til opplevinga av at førelesarar manglar ferdigheiter i språka. Desse utfordr­ing­ane vert diskutert i lys av Fricker (2007) sitt omgrep epistemisk urett. Til slutt argumenterer eg for at språkpolitikken i større grad må formulere tydelege kompetansemålsettingar (‘acquisition planning’), i tillegg til statusplanlegging.

Racial disparity in distant recurrence-free survival in localized breast cancer patients: A pooled analysis of NSABP trials

Background: Black race is associated with worse outcome in patients with breast cancer. We evaluated distant relapse-free survival (DRFS) between Black and White women with localized breast cancer who participated in NCI-sponsored clinical trials. Methods: We analyzed pooled data from eight National Surgical Adjuvant Breast and Bowel Project (NSABP) trials including 9,702 women with localized breast cancer treated with adjuvant chemotherapy (AC, n=7,485) or neoadjuvant chemotherapy (NAC, n=2,217), who self-reported as Black (n=1,070) or White (n=8,632). The association between race and DRFS was analyzed using log-rank tests and multivariate Cox regression. Results: After adjustment for covariates including age, tumor size, nodal status, body mass index and taxane use, and treatment (AC vs. NAC), Black race was associated with an inferior DRFS in ER-positive (HR 1.24 [95% CI 1.05-1.46], p=0.01), but not in ER-negative disease (HR 0.97 [95% CI 0.83-1.14], p=0.73), and significant interaction between race and ER status was observed (p=0.03). There was no racial disparity in DRFS among patients with pathologic complete response (pCR) (Log-rank p =0.8). For patients without pCR, black race was associated with worse DRFS in ER-positive (HR 1.67 [95% CI 1.14-2.45], p=0.01), but not in ER-negative disease (HR 0.91 [95% CI 0.65-1.28], p=0.59). Conclusion: Black race was associated with significantly inferior DRFS in ER-positive localized breast cancer treated with AC or NAC, but not in ER-negative disease. In the NAC group, racial disparity was also observed in patients with residual ER-positive breast cancer at surgery, but not in those who had a pathologic complete response.