Genomic and Transcriptomic Landscape of Triple-Negative Breast Cancers: Subtypes and Treatment Strategies

Jiang, Yi; Ma, Ding; Suo, Chen; Shi, Jianxin; Xue, Mengzhu; Hu, Xin; Xiao, Yi; Yu, Ke; Liu, Yi-Rong; Yu, Ying; Zheng, Yuanting; Li, Xiangnan; Zhang, Chenhui; Hu, Peng-Chen; Zhang, Jing; Hua, Qi; Zhang, Jiyang; Hou, Wanwan; Ren, Luyao; Bao, Ding; Li, Bingying; Yang, Jingcheng; Yao, Ling; Zuo, Wenbao; Zhao, Shen; Gong, Yue; Ren, Yi; Zhao, Yanqing; Yang, Yun; Niu, Zhenmin; Cao, Zhi; Stover, Daniel G.; Verschraegen, Claire F.; Kaklamani, Virginia; Daemen, Anneleen; Benson, John R.; Takabe, Kazuaki; Bai, Fan; Li, Da Qiang; Wang, Peng; Shi, Leming; Huang, Wei

doi:10.1016/j.ccell.2019.02.001

Cited by 672 publications

(814 citation statements)

References 62 publications

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“…Breast cancer stem cells (BCSCs) like normal stem cells, because of recruitment of the signaling pathways, are highly proliferative and dormant in most of the time that may lead to resist chemo‐ and radiotherapy (Zou et al, ). Triple‐negative breast cancer (TNBC) that lacking three important breast cells receptors is the most aggressive subtype, and there needs amenable targeted therapy (Jiang et al, ).…”

Section: Introductionmentioning

confidence: 99%

Suppressing the metastatic properties of the breast cancer cells using STAT3 decoy oligodeoxynucleotides: A promising approach for eradication of cancer cells by differentiation therapy

Rahmati

Johari

Kadivar

et al. 2020

Journal Cellular Physiology

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Due to the presence of cancer stem cells (CSCs), breast cancer often relapsed after conventional therapies. Strategies that induce differentiation of CSCs will be helpful in eradication of tumor cells, so we designed an oligodeoxynucleotide (ODNs) for targeting of signal transducer and activator of transcription 3 (STAT3) transcription factor which is involved in stemness, and constitutively activated in triple‐negative breast cancer. Molecular docking and electrophoretic mobility shift assay analysis showed that decoy ODN bound specifically to the DNA binding site of STAT3 protein. The prevalent uptake of Cy3‐labeled ODNs is in the cytoplasm and the nucleus of MDA‐MB‐231 treated cells. STAT3 decoy ODNs treatment showed cell growth inhibition by decreasing cell viability (17%), increasing the percentage of arrested cells in G0/G1 phases (18%), and triggering apoptosis (29%). Migration and invasion potential decreased from 10.77 to 6.76 µm/hr, by wound closure rate, and migrated/invaded percentage by 26.4% and 15.4% in the transwell assays, respectively. CD44 protein expression level on the cell surface also decreased, while CD24 increased. Mammosphere formation efficiency reduced in terms of tumorsphere size by 47%, while the required time increased. Cells morphology was changed, and lipid droplets were accumulated in the cytoplasm compared to the control and scrambled groups, in all assays (repeated triplicate). Furthermore, the gene expression of all downstream targets significantly decreased owing to suppressing the STAT3 transcription factor. Overall, the results confirmed the antitumor effects of STAT3 decoy in MDA‐MB‐231 cells. Thus, it seems that STAT3 decoy ODNs might be considered as an auxiliary tool for breast cancer eradicating by the differentiation therapy approach.

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Section: Introductionmentioning

confidence: 99%

Suppressing the metastatic properties of the breast cancer cells using STAT3 decoy oligodeoxynucleotides: A promising approach for eradication of cancer cells by differentiation therapy

Rahmati

Johari

Kadivar

et al. 2020

Journal Cellular Physiology

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show abstract

Section: Introductionmentioning

confidence: 99%

“…Breast cancers characterized by negative expression of estrogen receptor alpha (ERα), progesterone receptor (PR), and lack of amplification of human epidermal growth factor receptor 2 (HER2) are classified as triple-negative breast cancer (TNBC), a subtype of breast cancers. 1 This subtype represents 15% of all breast cancers and exhibits the most aggressive behavior among the four known subtypes of breast cancer. 2 Compared with other subtypes of breast cancer, TNBC is more prone to form distant metastasis, 3 especially in the lungs and brain, 4 both of which eventually lead to breast cancer-specific death in short-term.…”

Section: Introductionmentioning

confidence: 99%

GPER‐regulated lncRNA‐Glu promotes glutamate secretion to enhance cellular invasion and metastasis in triple‐negative breast cancer

Yin

Peng

et al. 2020

FASEB j.

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Triple‐negative breast cancer (TNBC) is a group of breast cancer with heterogeneity and poor prognosis and effective therapeutic targets are not available currently. TNBC has been recognized as estrogen‐independent breast cancer, while the novel estrogen receptor, namely G protein‐coupled estrogen receptor (GPER), was claimed to mediate estrogenic actions in TNBC tissues and cell lines. Through mRNA microarrays, lncRNA microarrays, and bioinformatics analysis, we found that GPER is activated by 17β‐estradiol (E2) and GPER‐specific agonist G1, which downregulates a novel lncRNA (termed as lncRNA‐Glu). LncRNA‐Glu can inhibit glutamate transport activity and transcriptional activity of its target gene VGLUT2 via specific binding. GPER‐mediated reduction of lncRNA‐Glu promotes glutamate transport activity and transcriptional activity of VGLUT2. Furthermore, GPER‐mediated activation of cAMP‐PKA signaling contributes to glutamate secretion. LncRNA‐Glu‐VGLUT2 signaling synergizes with cAMP‐PKA signaling to increase autologous glutamate secretion in TNBC cells, which activates glutamate N‐methyl‐D‐aspartate receptor (NMDAR) and its downstream CaMK and MEK‐MAPK pathways, thus enhancing cellular invasion and metastasis in vitro and in vivo. Our data provide new insights into GPER‐mediated glutamate secretion and its downstream signaling NMDAR‐CaMK/MEK‐MAPK during TNBC invasion. The mechanisms we discovered may provide new targets for clinical therapy of TNBC.

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“…We collected human samples from paired primary tumor and lung metastasis in one TNBC and four non‐TNBC patients. We macrodissected the specimens to avoid the contamination of stromal tissues (<30%) as previously described . Total DNA was extracted from fresh‐frozen tissues or formalin‐fixed paraffin‐embedded tissues using QIAamp DNA Mini Kits (Qiagen, Hilden, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…We macrodissected the specimens to avoid the contamination of stromal tissues (<30%) as previously described. 16 Total DNA was extracted from fresh-frozen tissues or formalin-fixed paraffinembedded tissues using QIAamp DNA Mini Kits (Qiagen, Hilden, Germany). DNA was quantified using a Qubit Fluorometer (Life Technologies, Carlsbad, CA).…”

Section: Samples Preparation and Wgsmentioning

confidence: 99%

Integration of whole‐genome sequencing and functional screening identifies a prognostic signature for lung metastasis in triple‐negative breast cancer

Xie

Yang

et al. 2019

Intl Journal of Cancer

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Lung metastasis is one of the leading causes of death for triple‐negative breast cancer (TNBC). We sought to characterize the genetic alterations underlying TNBC lung metastases by integrating whole‐genome sequencing and functional screening. Furthermore, we aimed to develop a metastasis‐related gene signature for TNBC patients to improve risk stratification. In this prospective observational study, we first conducted whole‐genome sequencing of paired primary tumor and lung metastasis from one TNBC patient to identify potential genetic driver alterations. An in vivo gain‐of‐function screening using an amplified open reading frame library was then employed to screen candidate genes promoting lung metastasis. Finally, we applied Cox proportional hazard regression modeling to develop a prognostic gene signature from 14 candidate genes in TNBC. Compared to the primary tumor, copy number amplifications of chromosomes 3q and 8q were identified in the lung metastasis. We discovered an enrichment of 14 genes from chromosomes 3q and 8q in mouse lung metastases model. We further developed and validated a four‐gene signature (ENY2, KCNK9, TNFRSF11B and KCNMB2) that predicts recurrence‐free survival and lung metastasis in TNBC. Our data also demonstrated that upregulated expression of ENY2 could promote invasion and lung metastasis of TNBC cells both in vitro and in vivo. In conclusion, our study reveals functional genes with copy number amplifications among chromosome 3q and 8q in lung metastasis of TNBC. And we develop a functional gene signature that can effectively stratify patients into low‐ and high‐risk subgroups of recurrence, helping frame personalized treatments for TNBC.

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Genomic and Transcriptomic Landscape of Triple-Negative Breast Cancers: Subtypes and Treatment Strategies

Cited by 672 publications

References 62 publications

Suppressing the metastatic properties of the breast cancer cells using STAT3 decoy oligodeoxynucleotides: A promising approach for eradication of cancer cells by differentiation therapy

Suppressing the metastatic properties of the breast cancer cells using STAT3 decoy oligodeoxynucleotides: A promising approach for eradication of cancer cells by differentiation therapy

GPER‐regulated lncRNA‐Glu promotes glutamate secretion to enhance cellular invasion and metastasis in triple‐negative breast cancer

Integration of whole‐genome sequencing and functional screening identifies a prognostic signature for lung metastasis in triple‐negative breast cancer

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