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Article ; Online: The WAVE3/β-catenin oncogenic signaling regulates chemoresistance in triple negative breast cancer.

Wang, Wei / Rana, Priyanka S / Markovic, Vesna / Sossey-Alaoui, Khalid

2023 Volume 25, Issue 1, Page(s) 31

Abstract: Background: Metastatic breast cancer is responsible for the death of the majority of breast cancer patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the USA and worldwide. Triple negative breast cancer (TNBC), ...

Abstract	Background: Metastatic breast cancer is responsible for the death of the majority of breast cancer patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the USA and worldwide. Triple negative breast cancer (TNBC), which lacks expression of hormone receptors (ER-α and PR) and ErbB2/HER2, is especially lethal due to its highly metastatic behavior, propensity to recur rapidly, and for its resistance to standard of care therapies, through mechanisms that remain incompletely understood. WAVE3 has been established as a promoter of TNBC development and metastatic progression. In this study, we investigated the molecular mechanisms whereby WAVE3 promotes therapy-resistance and cancer stemness in TNBC, through the regulation of β-catenin stabilization. Methods: The Cancer Genome Atlas dataset was used to assess the expression of WAVE3 and β-catenin in breast cancer tumors. Kaplan-Meier Plotter analysis was used to correlate expression of WAVE3 and β-catenin with breast cancer patients' survival probability. MTT assay was used to quantify cell survival. CRISPR/Cas9-mediated gene editing, 2D and 3D tumorsphere growth and invasion assays, Immunofluorescence, Western blotting, Semi-quantitative and real-time quantitative PCR analyses were applied to study the WAVE3/β-catenin oncogenic signaling in TNBC. Tumor xenograft assays were used to study the role of WAVE3 in mediating chemotherapy resistance of TNBC tumors. Results: Genetic inactivation of WAVE3 in combination of chemotherapy resulted in inhibition of 2D growth and 3D tumorsphere formation and invasion of TNBC cells in vitro, as well as tumor growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 did not. Further studies revealed that dual blocking of WAVE3 expression or phosphorylation in combination with chemotherapy treatment inhibited the activity and expression and stabilization of β-catenin. Most importantly, the combination of WAVE3-deficiency or WAVE3-phospho-deficiency and chemotherapy suppressed the oncogenic behavior of chemoresistant TNBC cells, both in vitro and in vivo. Conclusion: We identified a novel WAVE3/β-catenin oncogenic signaling axis that modulates chemoresistance of TNBC. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors.
MeSH term(s)	Female ; Humans ; beta Catenin/genetics ; beta Catenin/metabolism ; beta Catenin/therapeutic use ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm/genetics ; Neoplasm Recurrence, Local ; Signal Transduction ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/pathology
Chemical Substances	beta Catenin ; WASF3 protein, human ; CTNNB1 protein, human
Language	English
Publishing date	2023-03-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-023-01634-3
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Article ; Online: Selective fetal termination in monochorionic twin pregnancies - pregnancy outcome after bipolar cord coagulation and interstitial laser coagulation

Mandić-Marković Vesna / Miković Željko / Filimonović Dejan

Srpski Arhiv za Celokupno Lekarstvo, Vol 148, Iss 1-2, Pp 64-

2020 Volume 69

Abstract: Introduction/Objective. In this paper we present the perinatal outcome after selective fetal termination (SFT) in monochorionic (MH) twins done by bipolar cord coagulation (BCC) and interstitial laser coagulation (ILC). Methods. During a five-year period, ...

Abstract	Introduction/Objective. In this paper we present the perinatal outcome after selective fetal termination (SFT) in monochorionic (MH) twins done by bipolar cord coagulation (BCC) and interstitial laser coagulation (ILC). Methods. During a five-year period, SFT was done in 22 MH twins. BCC was done in 15 and ILC in seven cases. We registered the indication for SFT, gestational age at SFT, immediate postoperative death and late death of the co-twin, PPROM (preterm pre-labor rupture of membranes), gestational age at delivery/abortion, procedure-to-delivery interval, mode of delivery, neonatal body weight and 5-minute Apgar score. Results. Live birth was significantly higher after BCC than after ILC (86.7:57.1%). Gestational age at intervention was higher in BCC (20.2 ± 1.8 : 16.5 ± 1.7 weeks). Gestational age at delivery/abortion was lower for ILC (32.5 ± 4.8 : 27.5 ± 9.5 weeks); however, there was no difference when comparing live births only (33.8 ± 3.7 : 34.7 ± 4.5 weeks). There was no difference between procedure-to-delivery/abortion interval (86.7 ± 33.7 : 77.1 ± 73 days); however, the interval was significantly higher after ILC when comparing live births only (93.3 ± 33 : 133 ± 30.9 days). There was no difference in PPROM (26.7:14.3%); preterm delivery (69.2:50%); Cesarean section rate (84.6:75%); neonatal body weight (2174 ± 82.4 : 2475 ± 823 g); or Apgar score (7.7 ± 1.9 : 9.2 ± 1). Conclusion. There is no ideal method of SFT in MH twins. Success of each SFT method depends upon the correctly set indication, gestational age at the procedure, and the SFT technique. The risk of co-twin death is lower after BCC than after ILC. As in Narodni Front University Clinic for Gynecology and Obstetrics better results were achieved after BCC, this method became a standard for SFT in MH twins, except in cases of twin reversed arterial perfusion sequence before 16 weeks.
Keywords	selective fetal termination ; monochorionic twins ; bipolar cord coagulation ; interstitial laser coagulation ; Medicine ; R
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Serbian Medical Society
Document type	Article ; Online
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Article ; Online: The WAVE2/miR-29/Integrin-β1 Oncogenic Signaling Axis Promotes Tumor Growth and Metastasis in Triple-negative Breast Cancer.

Rana, Priyanka S / Wang, Wei / Markovic, Vesna / Szpendyk, Justin / Chan, Ernest Ricky / Sossey-Alaoui, Khalid

Cancer research communications

2023 Volume 3, Issue 1, Page(s) 160–174

Abstract: Breast cancer is the most frequently diagnosed malignancy in women and the major cause of death because of its invasion, metastasis, and resistance to therapies capabilities. The most aggressive subtype of breast cancer is triple-negative breast cancer ( ... ...

Abstract	Breast cancer is the most frequently diagnosed malignancy in women and the major cause of death because of its invasion, metastasis, and resistance to therapies capabilities. The most aggressive subtype of breast cancer is triple-negative breast cancer (TNBC) due to invasive and metastatic properties along with early age of diagnosis and poor prognosis. TNBC tumors do not express estrogen, progesterone, and HER2 receptors, which limits their treatment with targeted therapies. Cancer invasiveness and metastasis are known to be promoted by increased cell motility and upregulation of the WAVE proteins. While the contribution of WAVE2 to cancer progression is well documented, the WAVE2-mediated regulation of TNBC oncogenic properties is still under investigated, as does the molecular mechanisms by which WAVE2 regulates such oncogenic pathways. In this study, we show that WAVE2 plays a significant role in TNBC development, progression, and metastasis, through the regulation of miR-29 expression, which in turn targets Integrin-β1 ( Significance: Identification of a novel WAVE2/miR-29/
MeSH term(s)	Humans ; Female ; Triple Negative Breast Neoplasms/genetics ; Integrin beta1/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; MicroRNAs/genetics
Chemical Substances	Integrin beta1 ; MicroRNAs
Language	English
Publishing date	2023-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-22-0249
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Article ; Online: Suicide Bombing Terrorism - CORRIGENDUM.

Tin, Derrick / Galehan, Jordan / Markovic, Vesna / Ciottone, Gregory R

Prehospital and disaster medicine

2022 Volume 37, Issue 1, Page(s) 145–146

MeSH term(s)	Bombs ; Explosions ; Humans ; Suicide ; Terrorism
Language	English
Publishing date	2022-01-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	1025975-2
ISSN	1945-1938 ; 1049-023X
ISSN (online)	1945-1938
ISSN	1049-023X
DOI	10.1017/S1049023X22000176
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Article ; Online: Publisher Correction: Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer.

Kansakar, Urna / Wang, Wei / Markovic, Vesna / Sossey-Alaoui, Khalid

Scientific reports

2021 Volume 11, Issue 1, Page(s) 15800

Language	English
Publishing date	2021-07-29
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-94981-0
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Article ; Online: Phosphorylation of the proline-rich domain of WAVE3 drives its oncogenic activity in breast cancer.

Kansakar, Urna / Wang, Wei / Markovic, Vesna / Sossey-Alaoui, Khalid

Scientific reports

2021 Volume 11, Issue 1, Page(s) 3868

Abstract: Post-translational modification of proteins, such as tyrosine phosphorylation, plays a major role in driving the oncogenic activity of oncogenes. WAVE3 (WASF3), an adaptor and actin cytoskeleton remodeling protein, contributes to cell migration, cancer ... ...

Abstract	Post-translational modification of proteins, such as tyrosine phosphorylation, plays a major role in driving the oncogenic activity of oncogenes. WAVE3 (WASF3), an adaptor and actin cytoskeleton remodeling protein, contributes to cell migration, cancer cell invasion, and metastasis. WAVE3 plays a vital role in the progression and metastasis of triple negative breast cancer (TNBC), in part through the regulation of cancer stem cells (CSCs). Several studies have shown that WAVE3 tyrosine phosphorylation is required for its oncogenic activity. Moreover, our recent study showed that the proline rich domain (PRD) of WAVE3 is required for maintenance of the CSC niche in breast cancer by regulating the nuclear translocation of the CSC-specific nuclear transcription factor YB1. Here, we show that the PRD domain of WAVE3 and its phosphorylation are essential for driving the oncogenic activity of WAVE3. We show that phosphorylation of WAVE3 PRD is essential for migration and invasion of breast cancer cells in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, we show that phosphorylation of the WAVE3 PRD is essential for interaction between WAVE3 and YB1. Loss of PRD phosphorylation inhibits such interaction and the YB1-mediated activation of expression of CSC markers, as well as the WAVE3 mediated activation of EMT. Together, our study identifies a novel role of WAVE3 and its PRD domain in the regulation of the invasion metastasis cascade in BC that is independent of the known function of WAVE3 as an actin cytoskeleton remodeling protein through the WAVE regulatory complex (WRC).
MeSH term(s)	Animals ; Carcinogenesis/metabolism ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition ; Female ; Humans ; Mice ; Phosphorylation ; Platelet-Derived Growth Factor/metabolism ; Proline-Rich Protein Domains ; Protein-Tyrosine Kinases/metabolism ; Stem Cell Niche ; Triple Negative Breast Neoplasms/metabolism ; Wiskott-Aldrich Syndrome Protein Family/metabolism ; Y-Box-Binding Protein 1/metabolism
Chemical Substances	Platelet-Derived Growth Factor ; WASF3 protein, human ; Wasf3 protein, mouse ; Wiskott-Aldrich Syndrome Protein Family ; Y-Box-Binding Protein 1 ; Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2021-02-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-83479-4
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Article ; Online: Suicide Bombing Terrorism.

Tin, Derrick / Galehan, Jordan / Markovic, Vesna / Ciottone, Gregory R

Prehospital and disaster medicine

2021 Volume 36, Issue 6, Page(s) 664–668

Abstract: Introduction: While suicide bombings in the context of warfare have existed throughout history, there was an exponential rise in such attacks in the decade following the initiation of the War on Terror. The health care implications of such attacks are a ...

Abstract	Introduction: While suicide bombings in the context of warfare have existed throughout history, there was an exponential rise in such attacks in the decade following the initiation of the War on Terror. The health care implications of such attacks are a growing concern across the emergency response sector, and this study is an epidemiological examination of all terrorism-related bombings sustained from 1970-2019, comparing the rates of fatal injuries (FI) and non-fatal injuries (NFI) between suicide bombing attacks (SBA) versus non-suicide bombing attacks (NSBA). Method: Data collection was performed using a retrospective database search through the Global Terrorism Database (GTD). The GTD database was downloaded and searched using the internal database search functions for all events that occurred from January 1, 1970 - December 31, 2019. Bombing/explosion as a primary "attack type" and explosives as a primary "weapon type" were selected for the purpose of this study, and events were further sub-classified as either "suicide attack" or "non-suicide attack." Results were exported into an Excel spreadsheet (Microsoft Corp.; Redmond, Washington USA) for analysis. Findings: There were 82,217 bombing/explosion terrorist attacks using explosives documented during the study period with 135,807 fatalities and 352,500 NFI.A total of 5,416 events (6.59% of all events) were sub-classified as SBA causing 52,317 FI (38.52% of all FI) and 107,062 NFI (30.37% of all NFI).Mean SBA FI was 9.66 per event and mean SBA NFI was 19.77 per event compared to a mean NSBA FI of 1.09 per event and mean NSBA NFI of 3.20 per event. Conclusion: Suicide bombing attacks are a unique terrorist methodology that can inflict wide-spread psychological damage as well as significantly higher death and injury tolls when compared to more traditional NSBA. They have been increasing in popularity amongst terrorist organizations and groups, and Counter-Terrorism Medicine (CTM) specialists need to be aware of the unique injury patterns and potential risk mitigation strategies associated with SBA depending on the target type, location, and gender of the perpetrator.
MeSH term(s)	Blast Injuries/epidemiology ; Databases, Factual ; Explosions ; Humans ; Retrospective Studies ; Suicide ; Terrorism
Language	English
Publishing date	2021-10-22
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	1025975-2
ISSN	1945-1938 ; 1049-023X
ISSN (online)	1945-1938
ISSN	1049-023X
DOI	10.1017/S1049023X21001151
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Article ; Online: Diagnostic Tests in the Prediction of Neonatal Outcome in Early Placental Fetal Growth Restriction.

Mandić-Marković, Vesna / Bogavac, Mirjana / Miković, Željko / Panić, Milan / Pavlović, Dejan M / Mitrović, Jelena / Mandić, Milica

Medicina (Kaunas, Lithuania)

2023 Volume 59, Issue 2

Abstract: Background and ... ...

Abstract	Background and Objectives
MeSH term(s)	Infant, Newborn ; Pregnancy ; Humans ; Female ; Infant ; Fetal Growth Retardation ; Placenta ; Asphyxia/complications ; Gestational Age ; Diagnostic Tests, Routine ; Ultrasonography, Prenatal/adverse effects
Language	English
Publishing date	2023-02-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2188113-3
ISSN	1648-9144 ; 1010-660X
ISSN (online)	1648-9144
ISSN	1010-660X
DOI	10.3390/medicina59020406
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Article: Elucidating the molecular signaling pathways of WAVE3.

Kansakar, Urna / Wang, Wei / Markovic, Vesna / Sossey-Alaoui, Khalid

Annals of translational medicine

2020 Volume 8, Issue 14, Page(s) 900

Abstract: Cancer metastasis is a complex, multistep process that requires tumor cells to evade from the original site and form new tumors at a distant site or a different organ, often via bloodstream or the lymphatic system. Metastasis is responsible for more than ...

Abstract	Cancer metastasis is a complex, multistep process that requires tumor cells to evade from the original site and form new tumors at a distant site or a different organ, often via bloodstream or the lymphatic system. Metastasis is responsible for more than 90% of cancer-related deaths. WAVE3 belongs to the Wiskott-Aldrich syndrome protein (WASP) family, which regulate actin cytoskeleton remodeling as well as several aspects of cell migration, invasion, and metastasis. In fact, WAVE3 has been established as a driver of tumor progression and metastasis in cancers from several origins, including triple negative breast cancers (TNBCs), which are classified as the most lethal subtype of breast cancer, due to their resistance to standard of care therapy and highly metastatic behavior. In this review, we will attempt to summarize the recent advances that have been made to understand how WAVE3 contributes to the molecular mechanisms that control cancer progression and metastasis. We will also review the signaling pathways that are involved in the regulation of WAVE3 expression and function to identify potential therapeutic options targeted against WAVE3 for the treatment of patients with metastatic tumors.
Language	English
Publishing date	2020-08-10
Publishing country	China
Document type	Journal Article ; Review
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm.2020.02.16
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Article: Role of Kindlin-2 in cancer progression and metastasis.

Wang, Wei / Kansakar, Urna / Markovic, Vesna / Sossey-Alaoui, Khalid

Annals of translational medicine

2020 Volume 8, Issue 14, Page(s) 901

Abstract: Cancer metastasis is a complex and multistep process whereby cancer cells escape the confines of the primary site to establish a new residency at distant sites. This multistep process is also known as the invasion-metastasis cascade. The biological and ... ...

Abstract	Cancer metastasis is a complex and multistep process whereby cancer cells escape the confines of the primary site to establish a new residency at distant sites. This multistep process is also known as the invasion-metastasis cascade. The biological and molecular mechanisms that control the invasion-metastasis cascade, which ultimately leads to the spread of cancer cells into distant sites, remain poorly understood. Kindlin-2 (K2) belongs to the 4.1-ezrin-ridixin-moesin (FERM) domain family of proteins, which interact with the cytoplasmic tails of β-integrin subunits, leading to the activation of extensive biological functions. These biological functions include cell migration, differentiation, cancer initiation, development, and invasion. In this review, we will discuss the various molecular signaling pathways that are regulated by K2 during the invasion-metastasis cascade of cancer tumors. These signaling pathways include TGFβ, Wnt/β-Catenin, Hedgehog, p53 and senescence, and cancer stem cell (CSC) maintenance. We will also discuss the molecular signaling pathways that regulate K2 function both at the transcriptional and the posttranslational levels. Finally, we will consider molecular mechanisms to specifically target K2 as novel therapeutic options for cancer treatment.
Language	English
Publishing date	2020-08-13
Publishing country	China
Document type	Journal Article ; Review
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm.2020.03.64
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