A comparison of the molecular subtypes of triple-negative breast cancer among non-Asian and Taiwanese women

Tseng, Ling‐Ming; Chiu, Jen‐Hwey; Liu, Chunyu; Tsai, Yi‐Fang; Wang, Yunlin; Yang, Chu‐Wen; Shyr, Yi‐Ming

doi:10.1007/s10549-017-4195-7

Cited by 23 publications

(19 citation statements)

References 45 publications

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“…In particular, we showed that TNBC could be partitioned into five stable transcriptional subtypes with ∼25% being BL1, 25% IM, 16% LAR, 21% M and 13% MSL. Of note, the lack of reproducibility regarding BL2 and UNS subtypes has already been observed in other studies [ 4 , 15 ].…”

Section: Discussionmentioning

confidence: 55%

Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis

et al. 2018

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BackgroundRecent efforts of genome-wide gene expression profiling analyses have improved our understanding of the biological complexity and diversity of triple-negative breast cancers (TNBCs) reporting, at least six different molecular subtypes of TNBC namely Basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). However, little is known regarding the potential driving molecular events within each subtype, their difference in survival and response to therapy. Further insight into the underlying genomic alterations is therefore needed.Patients and methodsThis study was carried out using copy-number aberrations, somatic mutations and gene expression data derived from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas. TNBC samples (n = 550) were classified according to Lehmann’s molecular subtypes using the TNBCtype online subtyping tool (http://cbc.mc.vanderbilt.edu/tnbc/).ResultsEach subtype showed significant clinic-pathological characteristic differences. Using a multivariate model, IM subtype showed to be associated with a better prognosis (HR = 0.68; CI = 0.46–0.99; P = 0.043) whereas LAR subtype was associated with a worst prognosis (HR = 1.47; CI = 1.0–2.14; P = 0.046). BL1 subtype was found to be most genomically instable subtype with high TP53 mutation (92%) and copy-number deletion in genes involved in DNA repair mechanism (BRCA2, MDM2, PTEN, RB1 and TP53). LAR tumours were associated with higher mutational burden with significantly enriched mutations in PI3KCA (55%), AKT1 (13%) and CDH1 (13%) genes. M and MSL subtypes were associated with higher signature score for angiogenesis. Finally, IM showed high expression levels of immune signatures and check-point inhibitor genes such as PD1, PDL1 and CTLA4.ConclusionOur findings highlight for the first time the substantial genomic heterogeneity that characterize TNBC molecular subtypes, allowing for a better understanding of the disease biology as well as the identification of several candidate targets paving novel approaches for the development of anticancer therapeutics for TNBC.

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Section: Discussionmentioning

confidence: 55%

Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis

et al. 2018

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“…Lehman et al stated that the most appropriate subtype to study TNBC in relation to TGF-β signaling is a mesenchymal subtype. 29 Moreover, Tseng et al 30 reported the most common subtype of TNBC in the Taiwanese population is mesenchymal-like, while in Taiwanese population is mesenchymal type. Therefore, we chose mesenchymal TNBC cell line in our experiments.…”

Section: Discussionmentioning

confidence: 99%

<p>TGF-β-Induced TMEPAI Attenuates the Response of Triple-Negative Breast Cancer Cells to Doxorubicin and Paclitaxel</p>

Wardhani¹,

Puteri²,

Watanabe³

et al. 2020

JEP

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Purpose: Triple-negative breast cancer (TNBC) is a refractory type of breast cancer with poor prognosis and limited choice for treatment. Previous studies had shown that TNBC has high expressions of transmembrane prostate androgen-induced protein (TMEPAI). TMEPAI was known to be induced by TGF-β/Smad signaling and have tumorigenic functions that converting TGF-β from tumor suppressor to tumor promoter and inducing epithelialmesenchymal transition (EMT). Therefore, we aimed to define the role of TMEPAI in triple-negative breast cancer cells treatment using several anti-cancers in the presence of TGF-β. Methods: TMEPAI-knock out (KO) was carried out in a triple-negative breast cancer cell, BT549. TMEPAI editing was developed using the CRISPR-Cas9 system using two combinations of sgRNA to remove exon 4 of the TMEPAI gene entirely. Genotyping and proteomic analysis were performed to check the establishment of the TMEPAI-KO cells. Wild type (WT) and KO cells were used to determine inhibitory concentration 50% (IC 50) of several anti-cancers: doxorubicin, cisplatin, paclitaxel, and bicalutamide in the presence of TGF-β treatment. Results: KO cells were successfully established by completely removing the TMEPAI gene, which was proven in genomic and proteomic analysis. Further, in TMEPAI-KO cells, we found a significant reduction of IC 50 for doxorubicin and paclitaxel, and minimal effects were seen for cisplatin and bicalutamide. Our findings suggest that TGF-β-induced TMEPAI attenuates the response of TNBC to doxorubicin and paclitaxel, but not to cisplatin and bicalutamide. Conclusion: TGF-β induced TMEPAI contributes to the reduced response of TNBC treatment to doxorubicin and paclitaxel, but minimal on cisplatin and bicalutamide. Further study is needed to confirm our findings in other growth factor-induced cells, as well as in in vivo model.

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“…Triple negative breast cancer (TNBC) represents 15% − 20% of all newly diagnosed breast cancer patients and is characterized as a large tumor size, frequently diagnosed among younger women, and a poor prognosis with high metastases potential [2][3][4]. Recent investigations have demonstrated that TNBC may be composed of a number of distinct subtypes [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Interleukin 17A Promotes Cell Migration, Enhances anoikis resistance, and Favors Microenvironment for Triple Negative Breast Cancer Tumor Metastasis

Tsai

Huang

Lin

et al. 2020

Preprint

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Background: Our previous study demonstrated that overexpression of multiple epidermal growth factor-like domains 11 was involved the recurrence mechanism of triple negative breast cancer (TNBC) via up-regulation of cytokines and chemokines, including IL-17A signaling pathway. However, information concerning the role of IL-17A in tumor behavior or cancer microenvironment remains lacking. The aim of this study was to investigate the role of IL-17A on TNBC recurrent mechanisms, including tumor behavior, circulating tumor cells (CTCs), and cancer microenvironment. Methods: Using human TNBC MDA-MB-231 and MDA-MB-468 lines, the role of IL17-A was elucidated by knocked down IL-17A (DIL-17A) or administration of different dose of IL-17A in the culture medium. Cell proliferation, migration assay, Western blot analysis and Real-time PCR for IL-17A related signaling were evaluated. Three groups of implanted 4T1 cells in BALB/c mice were designed, namely, wild type (WT), DIL-17A, and WT + neutralizing IL-17 antibody (WT+Ab). Tumor weight, necrosis area, and the number of CTCs were measured. Immunohistochemistry or Western blot for CD34, CD8, and TGF-b1 were evaluated. Anoikis resistance was analyzed by live/dead stain and flow cytometry. Finally, clinic-pathological correlation between IL-17A expression and patients’ outcome such as disease free survival (DFS) and overall survival (OS) was performed by Kaplan-Meier’s method.Results: Our results demonstrated that IL-17A stimulated migratory activity, but not growth rate, of MDA-MB-231/468 cells via increased Src, Rho, and COX2 expression. In vivo, there was an increased necrosis area, a decreased tumor CD34 expression and CTCs in DIL-17A group; while there was a decreased tumor CD34 expression, CD8(+) cells, and CTCs, but an increased TGF-b1 expression in WT+Ab group, compared to the WT group. Knocked down-IL-17A also decreased anoikis resistance in human TNBC and murine 4T1 cell lines. Kaplan-Meier’s analysis disclosed a negative correlation between tumor IL-17A expression and OS in TNBC patients. Conclusion: We conclude that IL-17A promotes migratory and angiogenic activity in the tumors, enhances anoikis resistance, and modulates the immune landscape of tumor microenvironment favoring subsequent cancer metastasis. The blockade of IL-17A might provide a co-treatment target to prevent tumor metastasis or recurrence in TNBC patients.

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A comparison of the molecular subtypes of triple-negative breast cancer among non-Asian and Taiwanese women

Cited by 23 publications

References 45 publications

Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis

Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis

<p>TGF-β-Induced TMEPAI Attenuates the Response of Triple-Negative Breast Cancer Cells to Doxorubicin and Paclitaxel</p>

Interleukin 17A Promotes Cell Migration, Enhances anoikis resistance, and Favors Microenvironment for Triple Negative Breast Cancer Tumor Metastasis

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