The anti-androgen drug dutasteride renders triple negative breast cancer cells more sensitive to chemotherapy via inhibition of HIF-1α-/VEGF-signaling

Wahlde, Marie‐Kristin von; Hülsewig, Carolin; Rückert, Christian; Götte, Martin; Kiesel, L.; Bernemann, Christof

doi:10.3109/09513590.2014.971235

Cited by 25 publications

(14 citation statements)

References 17 publications

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“…It is important to emphasize that while there is approximately 80% overlap between TNBC and the basal breast cancer subtype, these two patterns of disease are not synonymous. Substantial diversity in histology and tumor biology exist within the group of cancers that are negative for all three tumor markers 3,4 , and genetic profiling studies are now defining TNBC subtypes that have varying degrees of chemosensitivity, risk of relapse, and response rates to neoadjuvant chemotherapy 5,7,14 .…”

Section: Discussionmentioning

confidence: 99%

“…Anderson Cancer Center 7 . Expression of the androgen receptor (AR) by IHC may therefore play a role in the clinical applicability of TNBC subtyping, and AR expression among TNBC cases opens the door to possible targeted anti-AR therapy for these tumors 9–11,14,16,17 . The mammary stem cell marker ALDH1 also appears to be prominent in differentiating the genetics of TNBC subtypes.…”

Section: Discussionmentioning

confidence: 99%

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Characterizing Breast Cancer in a Population with Increased Prevalence of Triple-Negative Breast Cancer: Androgen Receptor and ALDH1 Expression in Ghanaian Women

et al. 2015

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Introduction Androgen Receptor (AR) is the most commonly-expressed nuclear hormone receptor in breast cancer and may be a marker of response to targeted anti-androgen therapy, a particularly attractive option in the setting of triple negative breast cancer (TNBC). Gene expression studies suggest that AR-positivity may distinguish a luminal/AR TNBC subtype from mesenchymal, stem cell-like, and basal-like subtypes. Furthermore, frequency of TNBC is 2–3-times higher in African American and African compared to White American and European breast cancer pts, yet little is known regarding the distribution of TNBC subtypes in the high-risk African-ancestry populations. We sought to characterize AR expression and TNBC patterns among a series of breast cancers from Ghana, Africa. Methods Formalin-fixed, paraffin-embedded invasive breast cancer specimens from 147 pts treated at a single teaching hospital in Ghana were studied at a comprehensive cancer center in the United States and analyzed for estrogen receptor (ER), progesterone receptor (PR), HER2/neu, ALDH1 and AR expression via immunohistochemistry. Results Median patient age was 45 (range, 28–76yrs). Only 31 cases (21%) were ER-positive, and 14 (10%) were HER2-positive; 89 tumors (61%) were TNBC. For the entire group, 44% were AR-positive and 45% were ALDH1-positive. ER/PR-positive tumors were more likely to be AR-positive compared to ER/PR-negative tumors (87% versus 26%; p<0.0001) but there was no association between ALDH1 and AR expression. Among the TNBC cases, 45% were ALDH1-positive and 24% were AR-positive. ALDH1-positivity versus negativity was associated with AR-positivity within the subset of TNBC tumors (36% versus 14%; p=0.019). Conclusions We confirmed the results of others showing that the majority of African breast cancers are triple-negative. We also found that AR expression is lower than that reported in other populations. Surprisingly, a marker of mammary stem cell expression was found to correlate with AR expression among triple negative tumors in this series, suggesting that novel TNBC subtypes may be identified by studying TNBC patterns among more diverse international populations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Characterizing Breast Cancer in a Population with Increased Prevalence of Triple-Negative Breast Cancer: Androgen Receptor and ALDH1 Expression in Ghanaian Women

et al. 2015

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“…Another two mRNAs, HIF1A and IL8, both have important role in development of breast cancer (38)(39)(40)(41)(42). Studies have been reported that HIF1A is related to multidrug resistance, including paclitaxel (43)(44)(45). Further clarifying functions of these two lncRNAs might help understand the nature of TNBC and provide novel targets for treatment.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of Triple-Negative Breast Cancer Reveals an Integrated mRNA-lncRNA Signature with Predictive and Prognostic Value

et al. 2016

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While recognized as a generally aggressive disease, triplenegative breast cancer (TNBC) is highly diverse in different patients with variable outcomes. In this prospective observational study, we aimed to develop an RNA signature of TNBC patients to improve risk stratification and optimize the choice of adjuvant therapy. Transcriptome microarrays for 33 paired TNBC and adjacent normal breast tissue revealed tumor-specific mRNAs and long noncoding RNAs (lncRNA) that were associated with recurrence-free survival. Using the Cox regression model, we developed an integrated mRNA-lncRNA signature based on the mRNA species for FCGR1A, RSAD2, CHRDL1, and the lncRNA species for HIF1A-AS2 and AK124454. The prognostic and predictive accuracy of this signature was evaluated in a training set of 137 TNBC patients and then validated in a second independent set of 138 TNBC patients. In addition, we enrolled 82 TNBC patients who underwent taxane-based neoadjuvant chemotherapy (NCT) to further verify the predictive value of the signature. In both the training and validation sets, the integrated signature had better prognostic value than clinicopathologic parameters. We also confirmed the interaction between the administration of taxane-based NCT and different risk groups. In the NCT cohort, patients in the lowrisk group were more likely to achieve pathologic complete remission after taxane-based NCT (P ¼ 0.014). Functionally, we showed that HIF1A-AS2 and AK124454 promoted cell proliferation and invasion in TNBC cells and contributed there to paclitaxel resistance. Overall, our results established an integrated mRNA-lncRNA signature as a reliable tool to predict tumor recurrence and the benefit of taxane chemotherapy in TNBC, warranting further investigation in larger populations to help frame individualized treatments for TNBC patients.

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“…Hypoxia of tumor microenvironment has been considered to be the primary reason of chemoresistance, and evidences have shown that HIF1α could regulate the cellular response to hypoxic stress by mediating the expression of target genes, which is associated with angiogenesis, resistance, invasion and metastasis [28]. Moreover, inhibition of HIF1α was demonstrated to attenuate metastasis of breast cancer cells and increase the sensitivity of tumors to chemotherapy [29]. Recently, panobinostat (histone deacetylase inhibitor) was shown to reduce hypoxia-induced cisplatin resistance of NSCLC cells by destabilizing HIF1α expression [1], implying that HIF1α may play a key role in the drugresistance of NSCLC.…”

Section: Discussionmentioning

confidence: 99%

The combination therapy of HIF1α inhibitor LW6 and cisplatin plays an effective role on anti-tumor function in A549 cells

Mai¹,

Luo²,

Wu³

et al. 2019

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Hypoxia-inducible factor 1α (HIF1α) has been demonstrated to be involved in the resistance of various human cancer cells to chemotherapies. However, correlation between HIF1α and sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin has not been illuminated. The aim of present study was to investigate the effects of HIF1α on drug resistance in NSCLC cells. A549 cells were incubated in 21% or 0.5% O 2 followed by the assessment of HIF1α level with qRT-PCR and western blot, and ROS levels by DCFH-DA assays. Effects of hypoxia or HIF1α inhibitor LW6 on the proliferation and apoptosis of A549 cells were evaluated via CCK-8 and flow cytometry assays. IC 50 of A549 cells to cisplatin was determined by MTT assay. The mitochondrial membrane potential (MMP) was measured via JC-1 staining. Moreover, the expression of apoptosis related protein (Bcl-2, Bax) and drug resistance related proteins (MDR1, MRP1) were measured by western blotting. Exposure of A549 cells to 1% O 2 significantly upregulated HIF1α expression, maintained cell viability to cisplatin but decreased the ROS level, which promoted chemoresistance to cisplatin. LW6-treated A549 cells showed an increase in ROS level that blocked the hypoxia induced resistance to cisplatin and in addition, decreased expression of MDR1 and MRP1 in cisplatin-treated cells. This study revealed that hypoxia-improved cisplatin chemoresistance of NSCLC cells by regulated MDR1 and MRP1 expression via HIF1α/ROS pathway is reversed by LW6, suggesting that LW6 may act as effective sensitizer in chemotherapy for NSCLC.

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The anti-androgen drug dutasteride renders triple negative breast cancer cells more sensitive to chemotherapy via inhibition of HIF-1α-/VEGF-signaling

Abstract: Our results demonstrate that the SRD5A1-corresponding anti-androgenic drug dutasteride might act as a combinatorial therapeutic option besides standard chemotherapy in highly aggressive TNBC.

Cited by 25 publications

References 17 publications

Characterizing Breast Cancer in a Population with Increased Prevalence of Triple-Negative Breast Cancer: Androgen Receptor and ALDH1 Expression in Ghanaian Women

Characterizing Breast Cancer in a Population with Increased Prevalence of Triple-Negative Breast Cancer: Androgen Receptor and ALDH1 Expression in Ghanaian Women

Transcriptome Analysis of Triple-Negative Breast Cancer Reveals an Integrated mRNA-lncRNA Signature with Predictive and Prognostic Value

The combination therapy of HIF1α inhibitor LW6 and cisplatin plays an effective role on anti-tumor function in A549 cells

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