DACH1 inhibits breast cancer cell invasion and metastasis by down-regulating the transcription of matrix metalloproteinase 9

Aman, Sattout; Li, Yanan; Cheng, Yunmeng; Yang, Yanchun; Lv, Lei; Li, Bowen; Xia, Kangkai; Li, Shujing; Wu, Harry X.

doi:10.1038/s41420-021-00733-4

Cited by 22 publications

(27 citation statements)

References 47 publications

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“…Our results indicated that Dox dose-dependently decreased the expression of c-Jun in the nucleus extracts of both cellular variants ( Figure 3 F,G), which possibly explains the changes in MMP-9 secretion in the extracellular medium. Although a regulatory mechanism mediated by the AP-1 complex and, therefore c-Jun is carried out, other mechanisms could have also been involved, including the activity of the tumor suppressor DACH1 (Dachshund Homolog 1) [ 57 ], miR-194-5p [ 58 ], and decreases in sirtuin 6 [ 59 ]. Moreover, a potential association between PDCD4 and c-Jun signaling was suggested by the expression of miR-21, which promotes the migration, invasion, and angiogenic capacity of renal carcinoma cells [ 60 ].…”

Section: Resultsmentioning

confidence: 99%

eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model

González-Ortiz

Pulido-Capiz

Castañeda-Sánchez

et al. 2022

Cells

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Cells employ several adaptive mechanisms under conditions of accelerated cell division, such as the unfolded protein response (UPR). The UPR is composed of a tripartite signaling system that involves ATF6, PERK, and IRE1, which maintain protein homeostasis (proteostasis). However, deregulation of protein translation initiation could be associated with breast cancer (BC) chemoresistance. Specifically, eukaryotic initiation factor-4A (eIF4A) is involved in the unfolding of the secondary structures of several mRNAs at the 5′ untranslated region (5′-UTR), as well as in the regulation of targets involved in chemoresistance. Importantly, the tumor suppressor gene PDCD4 could modulate this process. This regulation might be disrupted in chemoresistant triple negative-BC (TNBC) cells. Therefore, we characterized the effect of doxorubicin (Dox), a commonly used anthracycline medication, on human breast carcinoma MDA-MB-231 cells. Here, we generated and characterized models of Dox chemoresistance, and chemoresistant cells exhibited lower Dox internalization levels followed by alteration of the IRE1 and PERK arms of the UPR and triggering of the antioxidant Nrf2 axis. Critically, chemoresistant cells exhibited PDCD4 downregulation, which coincided with a reduction in eIF4A interaction, suggesting a sophisticated regulation of protein translation. Likewise, Dox-induced chemoresistance was associated with alterations in cellular migration and invasion, which are key cancer hallmarks, coupled with changes in focal adhesion kinase (FAK) activation and secretion of matrix metalloproteinase-9 (MMP-9). Moreover, eIF4A knockdown via siRNA and its overexpression in chemoresistant cells suggested that eIF4A regulates FAK. Pro-atherogenic low-density lipoproteins (LDL) promoted cellular invasion in parental and chemoresistant cells in an MMP-9-dependent manner. Moreover, Dox only inhibited parental cell invasion. Significantly, chemoresistance was modulated by cryptotanshinone (Cry), a natural terpene purified from the roots of Salvia brandegeei. Cry and Dox co-exposure induced chemosensitization, connected with the Cry effect on eIF4A interaction. We further demonstrated the Cry binding capability on eIF4A and in silico assays suggest Cry inhibition on the RNA-processing domain. Therefore, strategic disruption of protein translation initiation is a druggable pathway by natural compounds during chemoresistance in TNBC. However, plasmatic LDL levels should be closely monitored throughout treatment.

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Section: Resultsmentioning

confidence: 99%

eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model

González-Ortiz

Pulido-Capiz

Castañeda-Sánchez

et al. 2022

Cells

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“…Moreover, further significantly upregulated genes such as DOCK10, GPC6, and FSCN1 have been related to enhanced tumor cell migration and/or invasion [67][68][69][70]. In contrast, several factors assigned to the suppression of tumor cell migration and/or invasion as well as angiogenesis, such as DLC1, RHOU, DACH1, and RECK, were significantly downregulated in the brain-seeking cell line in comparison with the native one [71][72][73][74][75][76].…”

Section: Discussionmentioning

confidence: 96%

Insights into the Steps of Breast Cancer–Brain Metastases Development: Tumor Cell Interactions with the Blood–Brain Barrier

Hamester

Stürken

Saygı

et al. 2022

IJMS

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Brain metastases (BM) represent a growing problem for breast cancer (BC) patients. Recent studies have demonstrated a strong impact of the BC molecular subtype on the incidence of BM development. This study explores the interaction between BC cells of different molecular subtypes and the blood–brain barrier (BBB). We compared the ability of BC cells of different molecular subtypes to overcome several steps (adhesion to the brain endothelium, disruption of the BBB, and invasion through the endothelial layer) during cerebral metastases formation, in vitro as well as in vivo. Further, the impact of these cells on the BBB was deciphered at the molecular level by transcriptome analysis of the triple-negative (TNBC) cells themselves as well as of hBMECs after cocultivation with BC cell secretomes. Compared to luminal BC cells, TNBC cells have a greater ability to influence the BBB in vitro and consequently develop BM in vivo. The brain-seeking subline and parental TNBC cells behaved similarly in terms of adhesion, whereas the first showed a stronger impact on the brain endothelium integrity and increased invasive ability. The comparative transcriptome revealed potential brain-metastatic-specific key regulators involved in the aforementioned processes, e.g., the angiogenesis-related factors TNXIP and CXCL1. In addition, the transcriptomes of the two TNBC cell lines strongly differed in certain angiogenesis-associated factors and in several genes related to cell migration and invasion. Based on the present study, we hypothesize that the tumor cell’s ability to disrupt the BBB via angiogenesis activation, together with increased cellular motility, is required for BC cells to overcome the BBB and develop brain metastases.

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“…Western blotting analysis showed that RARαS77A upregulated the epithelial marker E-cadherin while reducing the expression of ZEB1 (a transcriptional repressor that allows cancer cells to invade and spread) and the cytoskeletal protein β-catenin, both of which are reliable prognostic markers of solid tumor aggressiveness [25]. In addition, RARαS77A downregulated MMP2, a collagenase that can degrade the extracellular matrix to promote the invasion and metastasis of tumor cells [26,27]. Thus, the suppression of EMT is likely to be a major contributor to the antimetastatic action of RARαS77A.…”

Section: Discussionmentioning

confidence: 99%

Hypophosphorylation of retinoic acid receptor alpha inhibits triple-negative breast cancer cell migration and invasion

Ying

Zheng

et al. 2022

ARCH BIOL SCI BELGRA

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Retinoic acid receptor ? (RAR?) is a transcription factor that plays an essential role in tumor progression. Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma with a poor prognosis due to early therapeutic escape from conventional treatments and aggressive metastatic relapse by the occurrence of an epithelial-mesenchymal transition (EMT). However, as the expression level of RAR? does not correlate with the overall survival of TNBC patients, we speculate that post-translational modification such as phosphorylation of RAR? may be involved in EMT and TNBC metastasis. After overexpressing a phosphorylation-defective mutant of RAR? at serine 77 residue (RAR?S77A), we found that RAR? hypophosphorylation inhibited MDA-MB-231 cell motility and migration in vitro while reducing the lung metastatic potential in vivo. This was accompanied by increased expression of the epithelial marker E-cadherin and decreased expression of the mesenchymal markers ?-catenin and zinc finger E-box-binding homeobox 1 (ZEB1) in agreement with the suppression of EMT. Interestingly, the overexpression of wild-type RAR? in the presence of the RAR? agonist AM580 failed to suppress EMT and cell migration. These results indicate that hypophosphorylated RAR?S77 can directly mimic activated RAR? to inhibit EMT and migration/invasion of cells, thus providing a novel target in the therapeutic intervention of TNBC.

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DACH1 inhibits breast cancer cell invasion and metastasis by down-regulating the transcription of matrix metalloproteinase 9

Cited by 22 publications

References 47 publications

eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model

eIF4A/PDCD4 Pathway, a Factor for Doxorubicin Chemoresistance in a Triple-Negative Breast Cancer Cell Model

Insights into the Steps of Breast Cancer–Brain Metastases Development: Tumor Cell Interactions with the Blood–Brain Barrier

Hypophosphorylation of retinoic acid receptor alpha inhibits triple-negative breast cancer cell migration and invasion

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