RAC1 plays an essential role in estrogen receptor alpha function in breast cancer cells

Sun, Jun; Gaidosh, Gabriel; Xu, Ye; Mookhtiar, Adnan K.; Man, Na; Cingaram, Pradeep Reddy; Blumenthal, Ezra; Shiekhattar, Ramin; Goka, Erik T.; Nimer, Stephen D.; Lippman, Marc E.

doi:10.1038/s41388-021-01985-1

Cited by 8 publications

(9 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reduction in GPVI surface abundance could result from receptor shedding or internalisation. Thus, GPVI was investigated by Western blotting in both resting and stimulated platelets using an anti-GPVI-tail antibody [ 43 ]. The thiol-modifying agent NEM, a potent inducer of GPVI shedding, was used as a positive control ( Figure 2 B,C).…”

Section: Resultsmentioning

confidence: 99%

“…One of the most commonly used is EHT1864, a commercially available inhibitor that completely inhibits the GTP loading of Rac [ 41 ]. We have shown previously that a concentration higher than 100 μM EHT1864 causes off-target effects, such as cell apoptosis [ 42 ], limiting studies to 50 μM EHT1864 [ 43 , 44 , 45 , 46 ], which has been shown to be effective in platelets [ 47 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rac Inhibition Causes Impaired GPVI Signalling in Human Platelets through GPVI Shedding and Reduction in PLCγ2 Phosphorylation

Neagoe

Gardiner

Stegner

et al. 2022

IJMS

View full text Add to dashboard Cite

Rac1 is a small Rho GTPase that is activated in platelets upon stimulation with various ligands, including collagen and thrombin, which are ligands for the glycoprotein VI (GPVI) receptor and the protease-activated receptors, respectively. Rac1-deficient murine platelets have impaired lamellipodia formation, aggregation, and reduced PLCγ2 activation, but not phosphorylation. The objective of our study is to investigate the role of Rac1 in GPVI-dependent human platelet activation and downstream signalling. Therefore, we used human platelets stimulated using GPVI agonists (collagen and collagen-related peptide) in the presence of the Rac1-specific inhibitor EHT1864 and analysed platelet activation, aggregation, spreading, protein phosphorylation, and GPVI clustering and shedding. We observed that in human platelets, the inhibition of Rac1 by EHT1864 had no significant effect on GPVI clustering on collagen fibres but decreased the ability of platelets to spread or aggregate in response to GPVI agonists. Additionally, in contrast to what was observed in murine Rac1-deficient platelets, EHT1864 enhanced GPVI shedding in platelets and reduced the phosphorylation levels of PLCγ2 following GPVI activation. In conclusion, Rac1 activity is required for both human and murine platelet activation in response to GPVI-ligands, but Rac1’s mode of action differs between the two species.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rac Inhibition Causes Impaired GPVI Signalling in Human Platelets through GPVI Shedding and Reduction in PLCγ2 Phosphorylation

Neagoe

Gardiner

Stegner

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Additionally, siRNAs can also be used to evaluate a molecule's function in a biological pathway. For example, siRNA‐mediated Ras‐related C3 botulinum toxin substrate (RAC1) silencing in ER‐positive BC revealed its essential ER cofactor for ER protein stability and ER transcriptional activity (Sun et al, 2021).…”

Section: Clinical Application Of Rnai In Bcmentioning

confidence: 99%

RNA interference: Promising approach for breast cancer diagnosis and treatment

Allahyari

Velaei

Sanaat

et al. 2022

Cell Biology International

View full text Add to dashboard Cite

Today, cancer is one of the main health‐related challenges, and in the meantime, breast cancer (BC) is one of the most common cancers among women, with an alarming number of incidences and deaths every year. For this reason, the discovery of novel and more effective approaches for the diagnosis, treatment, and monitoring of the disease are very important. In this regard, scientists are looking for diagnostic molecules to achieve the above‐mentioned goals with higher accuracy and specificity. RNA interference (RNAi) is a posttranslational regulatory process mediated by microRNA intervention and small interfering RNAs. After transcription and edition, these two noncoding RNAs are integrated and activated with the RNA‐induced silencing complex (RISC) and AGO2 to connect the target mRNA by their complementary sequence and suppress their translation, thus reducing the expression of their target genes. These two RNAi categories show different patterns in different BC types and stages compared to healthy cells, and hence, these molecules have high diagnostic, monitoring, and therapeutic potentials. This article aims to review the RNAi pathway and diagnostic and therapeutic potentials with a special focus on BC.

show abstract

“…RAC1 signaling is upregulated in various cancers, including breast cancer [3][4][5][6][7], and regulates cellular processes such as tumor cell survival, proliferation and invasion [8]. Importantly, RAC1 is implicated in therapy resistance of tumor cells against both cytoablative [9][10][11] and targeted treatments [9,[12][13][14][15][16]. However, due to its almost ubiquitous expression and critical functions in various organ systems [17][18][19][20], there is little clinical relevance of potential RAC1-targeted treatments.…”

Section: Introductionmentioning

confidence: 99%

RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells

et al. 2023

View full text Add to dashboard Cite

Breast cancer stem cells (BCSC) are presumed to be responsible for treatment resistance, tumor recurrence and metastasis of breast tumors. However, development of BCSC-targeting therapies has been held back by their heterogeneity and the lack of BCSC-selective molecular targets. Here, we demonstrate that RAC1B, the only known alternatively spliced variant of the small GTPase RAC1, is expressed in a subset of BCSCs in vivo and its function is required for the maintenance of BCSCs and their chemoresistance to doxorubicin. In human breast cancer cell line MCF7, RAC1B is required for BCSC plasticity and chemoresistance to doxorubicin in vitro and for tumor-initiating abilities in vivo. Unlike Rac1, Rac1b function is dispensable for normal mammary gland development and mammary epithelial stem cell (MaSC) activity. In contrast, loss of Rac1b function in a mouse model of breast cancer hampers the BCSC activity and increases their chemosensitivity to doxorubicin treatment. Collectively, our data suggest that RAC1B is a clinically relevant molecular target for the development of BCSC-targeting therapies that may improve the effectiveness of doxorubicin-mediated chemotherapy.

show abstract

RAC1 plays an essential role in estrogen receptor alpha function in breast cancer cells

Cited by 8 publications

References 59 publications

Rac Inhibition Causes Impaired GPVI Signalling in Human Platelets through GPVI Shedding and Reduction in PLCγ2 Phosphorylation

Rac Inhibition Causes Impaired GPVI Signalling in Human Platelets through GPVI Shedding and Reduction in PLCγ2 Phosphorylation

RNA interference: Promising approach for breast cancer diagnosis and treatment

RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells

Contact Info

Product

Resources

About