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Article ; Online: Mutational processes of tobacco smoking and APOBEC activity generate protein-truncating mutations in cancer genomes.

Adler, Nina / Bahcheli, Alexander T / Cheng, Kevin C L / Al-Zahrani, Khalid N / Slobodyanyuk, Mykhaylo / Pellegrina, Diogo / Schramek, Daniel / Reimand, Jüri

Science advances

2023 Volume 9, Issue 44, Page(s) eadh3083

Abstract: Mutational signatures represent a genomic footprint of endogenous and exogenous mutational processes through tumor evolution. However, their functional impact on the proteome remains incompletely understood. We analyzed the protein-coding impact of ... ...

Abstract	Mutational signatures represent a genomic footprint of endogenous and exogenous mutational processes through tumor evolution. However, their functional impact on the proteome remains incompletely understood. We analyzed the protein-coding impact of single-base substitution (SBS) signatures in 12,341 cancer genomes from 18 cancer types. Stop-gain mutations (SGMs) (i.e., nonsense mutations) were strongly enriched in SBS signatures of tobacco smoking, APOBEC cytidine deaminases, and reactive oxygen species. These mutational processes alter specific trinucleotide contexts and thereby substitute serines and glutamic acids with stop codons. SGMs frequently affect cancer hallmark pathways and tumor suppressors such as
MeSH term(s)	Humans ; Mutation ; Neoplasms/genetics ; Neoplasms/pathology ; Cytidine Deaminase/genetics ; APOBEC Deaminases/genetics ; APOBEC Deaminases/metabolism ; Tobacco Smoking
Chemical Substances	APOBEC3A protein, human (EC 3.5.4.5) ; Cytidine Deaminase (EC 3.5.4.5) ; APOBEC Deaminases (EC 3.5.4.5)
Language	English
Publishing date	2023-11-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adh3083
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Article ; Online: The Ste20-like kinase - a Jack of all trades?

Garland, Brennan / Delisle, Samuel / Al-Zahrani, Khalid N / Pryce, Benjamin R / Sabourin, Luc A

Journal of cell science

2021 Volume 134, Issue 9

Abstract: Over the past 20 years, the Ste20-like kinase (SLK; also known as STK2) has emerged as a central regulator of cytoskeletal dynamics. Reorganization of the cytoskeleton is necessary for a plethora of biological processes including apoptosis, proliferation, ...

Abstract	Over the past 20 years, the Ste20-like kinase (SLK; also known as STK2) has emerged as a central regulator of cytoskeletal dynamics. Reorganization of the cytoskeleton is necessary for a plethora of biological processes including apoptosis, proliferation, migration, tissue repair and signaling. Several studies have also uncovered a role for SLK in disease progression and cancer. Here, we review the recent findings in the SLK field and summarize the various roles of SLK in different animal models and discuss the biochemical mechanisms regulating SLK activity. Together, these studies have revealed multiple roles for SLK in coupling cytoskeletal dynamics to cell growth, in muscle repair and in negative-feedback loops critical for cancer progression. Furthermore, the ability of SLK to regulate some systems appears to be kinase activity independent, suggesting that it may be an important scaffold for signal transduction pathways. These various findings reveal highly complex functions and regulation patterns of SLK in development and disease, making it a potential therapeutic target.
Language	English
Publishing date	2021-05-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.258269
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Article ; Online: Periostin gene expression in neu-positive breast cancer cells is regulated by a FGFR signaling cross talk with TGFβ/PI3K/AKT pathways.

Labrèche, Cédrik / Cook, David P / Abou-Hamad, John / Pascoal, Julia / Pryce, Benjamin R / Al-Zahrani, Khalid N / Sabourin, Luc A

Breast cancer research : BCR

2021 Volume 23, Issue 1, Page(s) 107

Abstract: Background: Breast cancer is a highly heterogeneous disease with multiple drivers and complex regulatory networks. Periostin (Postn) is a matricellular protein involved in a plethora of cancer types and other diseases. Postn has been shown to be ... ...

Abstract	Background: Breast cancer is a highly heterogeneous disease with multiple drivers and complex regulatory networks. Periostin (Postn) is a matricellular protein involved in a plethora of cancer types and other diseases. Postn has been shown to be involved in various processes of tumor development, such as angiogenesis, invasion, cell survival and metastasis. The expression of Postn in breast cancer cells has been correlated with a more aggressive phenotype. Despite extensive research, it remains unclear how epithelial cancer cells regulate Postn expression. Methods: Using murine tumor models and human TMAs, we have assessed the proportion of tumor samples that have acquired Postn expression in tumor cells. Using biochemical approaches and tumor cell lines derived from Neu+ murine primary tumors, we have identified major regulators of Postn gene expression in breast cancer cell lines. Results: Here, we show that, while the stromal compartment typically always expresses Postn, about 50% of breast tumors acquire Postn expression in the epithelial tumor cells. Furthermore, using an in vitro model, we show a cross-regulation between FGFR, TGFβ and PI3K/AKT pathways to regulate Postn expression. In HER2-positive murine breast cancer cells, we found that basic FGF can repress Postn expression through a PKC-dependent pathway, while TGFβ can induce Postn expression in a SMAD-independent manner. Postn induction following the removal of the FGF-suppressive signal is dependent on PI3K/AKT signaling. Conclusion: Overall, these results reveal a novel regulatory mechanism and shed light on how breast tumor cells acquire Postn expression. This complex regulation is likely to be cell type and cancer specific as well as have important therapeutic implications.
MeSH term(s)	Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Adhesion Molecules/genetics ; Cell Adhesion Molecules/metabolism ; Cell Line, Tumor ; Epithelial Cells/metabolism ; Female ; Fibroblast Growth Factors/pharmacology ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, ErbB-2/metabolism ; Receptors, Fibroblast Growth Factor/metabolism ; Signal Transduction/drug effects ; Transforming Growth Factor beta/metabolism ; Transforming Growth Factor beta/pharmacology
Chemical Substances	Cell Adhesion Molecules ; POSTN protein, human ; Receptors, Fibroblast Growth Factor ; Transforming Growth Factor beta ; Fibroblast Growth Factors (62031-54-3) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2021-11-22
Publishing country	England
Document type	Journal Article ; 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/s13058-021-01487-8
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Article ; Online: AKT-mediated phosphorylation of Sox9 induces Sox10 transcription in a murine model of HER2-positive breast cancer.

Al-Zahrani, Khalid N / Abou-Hamad, John / Pascoal, Julia / Labrèche, Cédrik / Garland, Brennan / Sabourin, Luc A

Breast cancer research : BCR

2021 Volume 23, Issue 1, Page(s) 55

Abstract: Background: Approximately 5-10% of HER2-positive breast cancers can be defined by low expression of the Ste20-like kinase, SLK, and high expression of SOX10. Our lab has observed that genetic deletion of SLK results in the induction of Sox10 and ... ...

Abstract	Background: Approximately 5-10% of HER2-positive breast cancers can be defined by low expression of the Ste20-like kinase, SLK, and high expression of SOX10. Our lab has observed that genetic deletion of SLK results in the induction of Sox10 and significantly accelerates tumor initiation in a HER2-induced mammary tumor model. However, the mechanism responsible for the induction of SOX10 gene expression in this context remains unknown. Methods: Using tumor-derived cell lines from MMTV-Neu mice lacking SLK and biochemical approaches, we have characterized the signaling mechanisms and relevant DNA elements driving Sox10 expression. Results: Biochemical and genetic analyses of the SOX10 regulatory region in SLK-deficient mammary tumor cells show that Sox10 expression is dependent on a novel -7kb enhancer that harbors three SoxE binding sites. ChIP analyses demonstrate that Sox9 is bound to those elements in vivo. Our data show that AKT can directly phosphorylate Sox9 in vitro at serine 181 and that AKT inhibition blocks Sox9 phosphorylation and Sox10 expression in SLK(-/-) tumor cells. AKT-mediated Sox9 phosphorylation increases its transcriptional activity on the Sox10 -7kb enhancer without altering its DNA-binding activity. Interestingly, analysis of murine and human mammary tumors reveals a direct correlation between the levels of active phospho-Sox9 S181 and Sox10 expression. Conclusions: Our results have identified a novel Sox10 enhancer and validated Sox9 as a direct target for AKT. As Sox10 is a biomarker for triple-negative breast cancers (TNBC), these findings might have major implications in the targeting and treatment of those cancers.
MeSH term(s)	Animals ; Binding Sites ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Enhancer Elements, Genetic ; Female ; Humans ; Mice ; Mice, Transgenic ; Phosphorylation ; Protein Serine-Threonine Kinases/deficiency ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, ErbB-2/metabolism ; SOX9 Transcription Factor/metabolism ; SOXE Transcription Factors/genetics ; Transcription, Genetic
Chemical Substances	SOX9 Transcription Factor ; SOXE Transcription Factors ; Sox10 protein, mouse ; Sox9 protein, mouse ; Erbb2 protein, mouse (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; SLK protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2021-05-13
Publishing country	England
Document type	Journal Article ; 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/s13058-021-01435-6
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Article ; Online: Correction to: AKT-mediated phosphorylation of Sox9 induces Sox10 transcription in a murine model of HER2-positive breast cancer.

Al-Zahrani, Khalid N / Abou-Hamad, John / Pascoal, Julia / Labrèche, Cédrik / Garland, Brennan / Sabourin, Luc A

Breast cancer research : BCR

2021 Volume 23, Issue 1, Page(s) 60

Language	English
Publishing date	2021-05-26
Publishing country	England
Document type	Published Erratum
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-021-01440-9
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Article ; Online: Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.

Lü, YiQing / Cho, Tiffany / Mukherjee, Saptaparna / Suarez, Carmen Florencia / Gonzalez-Foutel, Nicolas S / Malik, Ahmad / Martinez, Sebastien / Dervovic, Dzana / Oh, Robin Hyunseo / Langille, Ellen / Al-Zahrani, Khalid N / Hoeg, Lisa / Lin, Zhen Yuan / Tsai, Ricky / Mbamalu, Geraldine / Rotter, Varda / Ashton-Prolla, Patricia / Moffat, Jason / Chemes, Lucia Beatriz /

Gingras, Anne-Claude / Oren, Moshe / Durocher, Daniel / Schramek, Daniel

Molecular systems biology

2024

Abstract: Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly ... ...

Abstract	Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.
Language	English
Publishing date	2024-04-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2193510-5
ISSN	1744-4292 ; 1744-4292
ISSN (online)	1744-4292
ISSN	1744-4292
DOI	10.1038/s44320-024-00032-x
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Article ; Online: Assessing the efficacy of androgen receptor and Sox10 as independent markers of the triple-negative breast cancer subtype by transcriptome profiling.

Al-Zahrani, Khalid N / Cook, David P / Vanderhyden, Barbara C / Sabourin, Luc A

Oncotarget

2018 Volume 9, Issue 70, Page(s) 33348–33359

Abstract: The Androgen Receptor (AR) has recently garnered a lot of attention as a potential biomarker and therapeutic target in hormone-dependent cancers, including breast cancer. However, several inconsistencies exist within the literature as to which subtypes ... ...

Abstract	The Androgen Receptor (AR) has recently garnered a lot of attention as a potential biomarker and therapeutic target in hormone-dependent cancers, including breast cancer. However, several inconsistencies exist within the literature as to which subtypes of breast cancer express AR or whether it can be used to define its own unique subtype. Here, we analyze 1246 invasive breast cancer samples from the Cancer Genome Atlas and show that human breast cancers that have been subtyped based on their HER2, ESR1, or PGR expression contain four clusters of genes that are differentially expressed across all subtypes. We demonstrate that Sox10 is highly expressed in approximately one-third of all HER2/ESR1/PGR-low tumors and is a candidate biomarker of the triple-negative subtype. Although AR expression is acquired in many breast cancer cases, its expression could not define a unique subtype. Despite several reports stating that AR expression is acquired in HER2/ESR1/PGR triple-negative cancers, here we show that a low percentage of these cancers express AR (~20%). In contrast, AR is highly expressed in HER2-positive or ESR1/PGR-positive cancers (> 95%). Although AR expression cannot be used as an independent subtype biomarker, our analysis shows that routine evaluation of AR expression in tumors which express HER2, ESR1 and/or PGR may identify a unique subset of tumors which would benefit from anti-androgen based therapies.
Language	English
Publishing date	2018-09-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.26072
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Article ; Online: The LIM domain binding protein 1, Ldb1, has distinct roles in Neu-induced mammary tumorigenesis.

Ahmed, Sarra / Pryce, Benjamin R / Al-Zahrani, Khalid N / Sabourin, Luc A

Biochimica et biophysica acta. Molecular cell research

2018 Volume 1865, Issue 11 Pt A, Page(s) 1590–1597

Abstract: We have previously shown that the Ste20-like kinase SLK interacts directly with the LIM domain-binding protein 1, Ldb1. Ldb1 knock down in murine fibroblasts activates SLK and enhances cell migration. To investigate the effect of Ldb1 deletion in ErbB2/ ... ...

Abstract	We have previously shown that the Ste20-like kinase SLK interacts directly with the LIM domain-binding protein 1, Ldb1. Ldb1 knock down in murine fibroblasts activates SLK and enhances cell migration. To investigate the effect of Ldb1 deletion in ErbB2/HER2-driven tumorigenesis, Ldb1 conditional mice were crossed into MMTV-NIC mice, expressing the Neu oncogene and Cre recombinase from a bi-cistronic transgene. Our results show that Ldb1 is expressed in the mammary epithelium and that deletion of Ldb1 does not impair mammary gland development. Although high levels of Ldb1 can be correlated with poor prognosis in HER2+ breast cancers, Ldb1 ablation does not affect Neu-induced tumor progression in transgenic mice. Surprisingly, Ldb1 deletion did not affect SLK kinase activity in primary tumors or established cell lines. Nevertheless, Ldb1-deficient tumor cells showed enhanced mesenchymal and migratory characteristics in vitro. However, Ldb1-null cells failed to colonize the lungs of wildtype female mice when injected into the tail vein. Together our results show that Ldb1 is dispensable for mammary gland development and Neu-induced tumor progression but required for dissemination at secondary sites. Furthermore, our data also highlight contrasting cell line behaviours observed from in vivo and in vitro assays.
MeSH term(s)	Animals ; Cell Line ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Disease Models, Animal ; Epithelial-Mesenchymal Transition ; Gene Targeting ; Heterografts ; LIM Domain Proteins/genetics ; LIM Domain Proteins/metabolism ; Mice ; Mice, Knockout ; Mice, Transgenic ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Protein-Serine-Threonine Kinases/genetics ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism
Chemical Substances	DNA-Binding Proteins ; LIM Domain Proteins ; Ldb1 protein, mouse ; Receptor, ErbB-2 (EC 2.7.10.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; SLK protein, mouse (EC 2.7.11.1)
Language	English
Publishing date	2018-08-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2018.08.013
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Article ; Online: Transforming growth factor β-induced epithelial to mesenchymal transition requires the Ste20-like kinase SLK independently of its catalytic activity.

Conway, Jillian / Al-Zahrani, Khalid N / Pryce, Benjamin R / Abou-Hamad, John / Sabourin, Luc A

Oncotarget

2017 Volume 8, Issue 58, Page(s) 98745–98756

Abstract: Invasion can be ... ...

Abstract	Invasion can be stimulated
Language	English
Publishing date	2017-11-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.21928
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Article ; Online: Differential DNA damage repair and PARP inhibitor vulnerability of the mammary epithelial lineages.

Kim, Hyeyeon / Aliar, Kazeera / Tharmapalan, Pirashaanthy / McCloskey, Curtis W / Kuttanamkuzhi, Abhijith / Grünwald, Barbara T / Palomero, Luis / Mahendralingam, Mathepan J / Waas, Matthew / Mer, Arvind S / Elliott, Mitchell J / Zhang, Bowen / Al-Zahrani, Khalid N / Langille, Ellen R / Parsons, Michael / Narala, Swami / Hofer, Stefan / Waterhouse, Paul D / Hakem, Razqallah /

Haibe-Kains, Benjamin / Kislinger, Thomas / Schramek, Daniel / Cescon, David W / Pujana, Miquel A / Berman, Hal K / Khokha, Rama

Cell reports

2023 Volume 42, Issue 10, Page(s) 113256

Abstract: It is widely assumed that all normal somatic cells can equally perform homologous recombination (HR) and non-homologous end joining in the DNA damage response (DDR). Here, we show that the DDR in normal mammary gland inherently depends on the epithelial ... ...

Abstract	It is widely assumed that all normal somatic cells can equally perform homologous recombination (HR) and non-homologous end joining in the DNA damage response (DDR). Here, we show that the DDR in normal mammary gland inherently depends on the epithelial cell lineage identity. Bioinformatics, post-irradiation DNA damage repair kinetics, and clonogenic assays demonstrated luminal lineage exhibiting a more pronounced DDR and HR repair compared to the basal lineage. Consequently, basal progenitors were far more sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis) in both mouse and human mammary epithelium. Furthermore, PARPi sensitivity of murine and human breast cancer cell lines as well as patient-derived xenografts correlated with their molecular resemblance to the mammary progenitor lineages. Thus, mammary epithelial cells are intrinsically divergent in their DNA damage repair capacity and PARPi vulnerability, potentially influencing the clinical utility of this targeted therapy.
MeSH term(s)	Humans ; Animals ; Mice ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Antineoplastic Agents/pharmacology ; DNA Repair ; Homologous Recombination ; DNA Damage
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; Antineoplastic Agents
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.113256
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