Publications by authors named "Veronique Ouellet"

45 Publications

CdGAP promotes prostate cancer metastasis by regulating epithelial-to-mesenchymal transition, cell cycle progression, and apoptosis.

Commun Biol 2021 09 7;4(1):1042. Epub 2021 Sep 7.

Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.

High mortality of prostate cancer patients is primarily due to metastasis. Understanding the mechanisms controlling metastatic processes remains essential to develop novel therapies designed to prevent the progression from localized disease to metastasis. CdGAP plays important roles in the control of cell adhesion, migration, and proliferation, which are central to cancer progression. Here we show that elevated CdGAP expression is associated with early biochemical recurrence and bone metastasis in prostate cancer patients. Knockdown of CdGAP in metastatic castration-resistant prostate cancer (CRPC) PC-3 and 22Rv1 cells reduces cell motility, invasion, and proliferation while inducing apoptosis in CdGAP-depleted PC-3 cells. Conversely, overexpression of CdGAP in DU-145, 22Rv1, and LNCaP cells increases cell migration and invasion. Using global gene expression approaches, we found that CdGAP regulates the expression of genes involved in epithelial-to-mesenchymal transition, apoptosis and cell cycle progression. Subcutaneous injection of CdGAP-depleted PC-3 cells into mice shows a delayed tumor initiation and attenuated tumor growth. Orthotopic injection of CdGAP-depleted PC-3 cells reduces distant metastasic burden. Collectively, these findings support a pro-oncogenic role of CdGAP in prostate tumorigenesis and unveil CdGAP as a potential biomarker and target for prostate cancer treatments.
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http://dx.doi.org/10.1038/s42003-021-02520-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423782PMC
September 2021

Expression of ERBB Family Members as Predictive Markers of Prostate Cancer Progression and Mortality.

Cancers (Basel) 2021 Apr 2;13(7). Epub 2021 Apr 2.

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) et Institut du Cancer de Montréal (ICM), Montreal, QC H2X 0A9, Canada.

Background: EGFR, ERBB2, ERBB3, and ERBB4 are growth receptors of the ERBB family implicated in the development of epithelial cancers. Studies have suggested a role for EGFR and ERBB3 in the development of prostate cancer (PC), while the involvement of ERBB2 and ERBB4 remains unclear. In this study, we evaluated the expression of all members of the ERBB family in PC tissue from a large cohort and determined their contribution, alone or in combination, as prognostic markers.

Methods: Using immunofluorescence coupled with digital image analyses, we quantified the expression of EGFR, ERBB2, ERBB3, and ERBB4 on radical prostatectomy specimens ( = 285) arrayed on six tissue microarrays. By combining EGFR, ERBB2, and ERBB3 protein expression in a decision tree model, we identified an association with biochemical recurrence (log rank = 25.295, < 0.001), development of bone metastases (log rank = 23.228, < 0.001), and cancer-specific mortality (log rank = 24.586, < 0.001).

Conclusions: Our study revealed that specific protein expression patterns of ERBB family members are associated with an increased risk of PC progression and mortality.
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http://dx.doi.org/10.3390/cancers13071688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038288PMC
April 2021

Elevated Expression of Glycerol-3-Phosphate Phosphatase as a Biomarker of Poor Prognosis and Aggressive Prostate Cancer.

Cancers (Basel) 2021 Mar 13;13(6). Epub 2021 Mar 13.

Institut du Cancer de Montréal, Montreal, QC H2X 0A9, Canada.

The limitations of the biomarker prostate-specific antigen (PSA) necessitate the pursuit of biomarkers capable of better identifying high-risk prostate cancer (PC) patients in order to improve their therapeutic management and outcomes. Aggressive prostate tumors characteristically exhibit high rates of glycolysis and lipogenesis. Glycerol 3-phosphate phosphatase (G3PP), also known as phosphoglycolate phosphatase (PGP), is a recently identified mammalian enzyme, shown to play a role in the regulation of glucose metabolism, lipogenesis, lipolysis, and cellular nutrient-excess detoxification. We hypothesized that G3PP may relieve metabolic stress in cancer cells and assessed the association of its expression with PC patient prognosis. Using immunohistochemical staining, we assessed the epithelial expression of G3PP in two different radical prostatectomy (RP) cohorts with a total of 1797 patients, for whom information on biochemical recurrence (BCR), metastasis, and mortality was available. The association between biomarker expression, biochemical recurrence (BCR), bone metastasis, and prostate cancer-specific survival was established using log-rank and multivariable Cox regression analyses. High expression of G3PP in PC epithelial cells is associated with an increased risk of BCR, bone metastasis, and PC-specific mortality. Multivariate analysis revealed high G3PP expression in tumors as an independent predictor of BCR and bone metastasis development. High G3PP expression in tumors from patients eligible for prostatectomies is a new and independent prognostic biomarker of poor prognosis and aggressive PC for recurrence, bone metastasis, and mortality.
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http://dx.doi.org/10.3390/cancers13061273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000625PMC
March 2021

Endocrine Signals Altered by Heat Stress Impact Dairy Cow Mammary Cellular Processes at Different Stages of the Dry Period.

Animals (Basel) 2021 Feb 21;11(2). Epub 2021 Feb 21.

Department of Animal Sciences, University of Florida, Gainesville, FL 32611, USA.

Hormonal alterations occurring under late gestation heat stress may disturb mammary gland remodelling, resulting in a reduced milk yield during the subsequent lactation. We investigated the effects of an altered endocrine environment on mammary gene expression at different stages of the dry period. Mammary gland biopsies from in vivo-cooled (CL) or heat-stressed (HT) cows were collected at d 3 and 35 relative to dry-off and divided into explants. Explants were incubated in vitro for 24 h in one of three media: Basal: no prolactin or estrogen; CL-mimic: Basal + low prolactin + high 17β-estradiol, or HT-mimic: Basal + high prolactin + low 17β-estradiol. Real time qPCR was used to quantify gene expression. We established that late-gestation heat stress changes the expression of prolactin and oestrogen receptors, downregulates genes involved in apoptosis, autophagy and proliferation at d 3 and upregulates genes related to those cellular processes at d 35. Moreover, compared with in vivo treatments, we showed that the expression of fewer genes was impacted by in vitro treatments which aimed to mimic the hormonal response of cows exposed to a different environment. Further research will continue to uncover the mechanisms behind the production impairments caused by late-gestation heat stress.
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http://dx.doi.org/10.3390/ani11020563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930950PMC
February 2021

Comparing Perspectives of Canadian Men Diagnosed With Prostate Cancer and Health Care Professionals About Active Surveillance.

J Patient Exp 2020 Dec 11;7(6):1122-1129. Epub 2020 Jun 11.

Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, Quebec, Canada.

Active surveillance (AS) has gained acceptance as a primary management approach for patients diagnosed with low-risk prostate cancer (PC). In this qualitative study, we compared perspectives between patients and health care professionals (HCP) to identify what may contribute to patient-provider discordance, influence patient decision-making, and interfere with the uptake of AS. We performed a systematic comparison of perspectives about AS reported from focus groups with men eligible for AS (7 groups, N = 52) and HCP (5 groups, N = 48) who engaged in conversations about AS with patient. We used conventional content analysis to scrutinize separately focus group transcripts and reached a consensus on similar or divergent viewpoints between them. Patients and clinicians agreed that AS was appropriate for low grade PC and understood the low-risk nature of the disease. They shared the perspective that disease status was a critical factor to pursue or discontinue AS. However, men expressed a greater emphasis on quality of life in their decisions related to AS. Patients and clinicians differed in their perspectives on the clarity, availability, and volume of information needed and offered; clinicians acknowledged variations between HCP when presenting AS, while patients were often compelled to seek additional information beyond what was provided by physicians and experienced difficulty in finding or interpreting information applicable to their situation. A greater understanding of discordant perspectives about AS between patients and HCP can help improve patient engagement and education, inform development of knowledge-based tools or aids for decision-making, and identify areas that require standardization across the clinical practice.
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http://dx.doi.org/10.1177/2374373520932735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786672PMC
December 2020

Invasive growth associated with cold-inducible RNA-binding protein expression drives recurrence of surgically resected brain metastases.

Neuro Oncol 2021 09;23(9):1470-1480

Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.

Background: Sixty percent of surgically resected brain metastases (BrM) recur within 1 year. These recurrences have long been thought to result from the dispersion of cancer cells during surgery. We tested the alternative hypothesis that invasion of cancer cells into the adjacent brain plays a significant role in local recurrence and shortened overall survival.

Methods: We determined the invasion pattern of 164 surgically resected BrM and correlated with local recurrence and overall survival. We performed single-cell RNA sequencing (scRNAseq) of >15,000 cells from BrM and adjacent brain tissue. Validation of targets was performed with a novel cohort of BrM patient-derived xenografts (PDX) and patient tissues.

Results: We demonstrate that invasion of metastatic cancer cells into the adjacent brain is associated with local recurrence and shortened overall survival. scRNAseq of paired tumor and adjacent brain samples confirmed the existence of invasive cancer cells in the tumor-adjacent brain. Analysis of these cells identified cold-inducible RNA-binding protein (CIRBP) overexpression in invasive cancer cells compared to cancer cells located within the metastases. Applying PDX models that recapitulate the invasion pattern observed in patients, we show that CIRBP is overexpressed in highly invasive BrM and is required for efficient invasive growth in the brain.

Conclusions: These data demonstrate peritumoral invasion as a driver of treatment failure in BrM that is functionally mediated by CIRBP. These findings improve our understanding of the biology underlying postoperative treatment failure and lay the groundwork for rational clinical trial development based upon invasion pattern in surgically resected BrM.
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http://dx.doi.org/10.1093/neuonc/noab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408858PMC
September 2021

PUMA and NOXA Expression in Tumor-Associated Benign Prostatic Epithelial Cells Are Predictive of Prostate Cancer Biochemical Recurrence.

Cancers (Basel) 2020 Oct 29;12(11). Epub 2020 Oct 29.

Centre de Recherche du Centre Hospitalier de L'Université de Montréal (CRCHUM) et Institut du Cancer de Montréal (ICM), Montreal, QC H2X 0A9, Canada.

Background: Given that treatment decisions in prostate cancer (PC) are often based on risk, there remains a need to find clinically relevant prognostic biomarkers to stratify PC patients. We evaluated PUMA and NOXA expression in benign and tumor regions of the prostate using immunofluorescence techniques and determined their prognostic significance in PC.

Methods: PUMA and NOXA expression levels were quantified on six tissue microarrays (TMAs) generated from radical prostatectomy samples ( = 285). TMAs were constructed using two cores of benign tissue and two cores of tumor tissue from each patient. Association between biomarker expression and biochemical recurrence (BCR) at 3 years was established using log-rank (LR) and multivariate Cox regression analyses.

Results: Kaplan-Meier analysis showed a significant association between BCR and extreme levels (low or high) of PUMA expression in benign epithelial cells (LR = 8.831, = 0.003). Further analysis revealed a significant association between high NOXA expression in benign epithelial cells and BCR (LR = 14.854, < 0.001). The combination of extreme PUMA and high NOXA expression identified patients with the highest risk of BCR (LR = 16.778, < 0.001) in Kaplan-Meier and in a multivariate Cox regression analyses (HR: 2.935 (1.645-5.236), < 0.001).

Conclusions: The combination of PUMA and NOXA protein expression in benign epithelial cells was predictive of recurrence following radical prostatectomy and was independent of PSA at diagnosis, Gleason score and pathologic stage.
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http://dx.doi.org/10.3390/cancers12113187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692508PMC
October 2020

Risk Stratification of Prostate Cancer Through Quantitative Assessment of PTEN Loss (qPTEN).

J Natl Cancer Inst 2020 11;112(11):1098-1104

Division of Cancer Biology & Genetics, Queen's Cancer Research Institute, Kingston, ON K7L 3N6, Canada.

Background: Phosphatase and tensin homolog (PTEN) loss has long been associated with adverse findings in early prostate cancer. Studies to date have yet to employ quantitative methods (qPTEN) for measuring of prognostically relevant amounts of PTEN loss in postsurgical settings and demonstrate its clinical application.

Methods: PTEN protein levels were measured by immunohistochemistry in radical prostatectomy samples from training (n = 410) and validation (n = 272) cohorts. PTEN loss was quantified per cancer cell and per tissue microarray core. Thresholds for identifying clinically relevant PTEN loss were determined using log-rank statistics in the training cohort. Univariate (Kaplan-Meier) and multivariate (Cox proportional hazards) analyses on various subpopulations were performed to assess biochemical recurrence-free survival (BRFS) and were independently validated. All statistical tests were two-sided.

Results: PTEN loss in more than 65% cancer cells was most clinically relevant and had statistically significant association with reduced BRFS in training (hazard ratio [HR] = 2.48, 95% confidence interval [CI] = 1.59 to 3.87; P < .001) and validation cohorts (HR = 4.22, 95% CI = 2.01 to 8.83; P < .001). The qPTEN scoring method identified patients who recurred within 5.4 years after surgery (P < .001). In men with favorable risk of biochemical recurrence (Cancer of the Prostate Risk Assessment - Postsurgical scores <5 and no adverse pathological features), qPTEN identified a subset of patients with shorter BRFS (HR = 5.52, 95% CI = 2.36 to 12.90; P < .001) who may be considered for intensified monitoring and/or adjuvant therapy.

Conclusions: Compared with previous qualitative approaches, qPTEN improves risk stratification of postradical prostatectomy patients and may be considered as a complementary tool to guide disease management after surgery.
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http://dx.doi.org/10.1093/jnci/djaa032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669224PMC
November 2020

V-ATPase-associated prorenin receptor is upregulated in prostate cancer after PTEN loss.

Oncotarget 2019 Aug 13;10(48):4923-4936. Epub 2019 Aug 13.

Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada.

Phosphatase and tensin homolog (PTEN) tumor suppressor protein loss is common in prostate cancer (PCa). PTEN loss increases PI3K/Akt signaling, which promotes cell growth and survival. To find secreted biomarkers of PTEN loss, a proteomic screen was used to compare secretomes of cells with and without PTEN expression. We showed that PTEN downregulates Prorenin Receptor (PRR) expression and secretion of soluble Prorenin Receptor (sPRR) in PCa cells and in mouse. PRR is an accessory protein required for assembly of the vacuolar ATPase (V-ATPase) complex. V-ATPase is required for lysosomal acidification, amino acid sensing, efficient mechanistic target of Rapamycin complex 1 (mTORC1) activation, and β-Catenin signaling. On PCa tissue microarrays, PRR expression displayed a positive correlation with Akt phosphorylation. Moreover, PRR expression was required for proliferation of PCa cells by maintaining V-ATPase function. Further, we provided evidence for a potential clinical role for PRR expression and sPRR concentration in differentiating low from high Gleason grade PCa. Overall, the current study unveils a mechanism by which PTEN can inhibit tumor growth. Lower levels of PRR result in attenuated V-ATPase activity and reduced PCa cell proliferation.
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http://dx.doi.org/10.18632/oncotarget.27075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697641PMC
August 2019

Validation of the prognostic value of NF-κB p65 in prostate cancer: A retrospective study using a large multi-institutional cohort of the Canadian Prostate Cancer Biomarker Network.

PLoS Med 2019 07 2;16(7):e1002847. Epub 2019 Jul 2.

Centre de recherche du Centre hospitalier de l'Université de Montréal, Centre hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.

Background: The identification of patients with high-risk prostate cancer (PC) is a major challenge for clinicians, and the improvement of current prognostic parameters is an unmet clinical need. We and others have identified an association between the nuclear localization of NF-κB p65 and biochemical recurrence (BCR) in PC in small and/or single-centre cohorts of patients.

Methods And Findings: In this study, we accessed 2 different multi-centre tissue microarrays (TMAs) representing cohorts of patients (Test-TMA and Validation-TMA series) of the Canadian Prostate Cancer Biomarker Network (CPCBN) to validate the association between p65 nuclear frequency and PC outcomes. Immunohistochemical staining of p65 was performed on the Test-TMA and Validation-TMA series, which include PC tissues from patients treated by first-line radical prostatectomy (n = 250 and n = 1,262, respectively). Two independent observers evaluated the p65 nuclear frequency in digital images of cancer tissue and benign adjacent gland tissue. Kaplan-Meier curves coupled with a log-rank test and univariate and multivariate Cox regression models were used for statistical analyses of continuous values and dichotomized data (cutoff of 3%). Multivariate analysis of the Validation-TMA cohort showed that p65 nuclear frequency in cancer cells was an independent predictor of BCR using continuous (hazard ratio [HR] 1.02 [95% CI 1.00-1.03], p = 0.004) and dichotomized data (HR 1.33 [95% CI 1.09-1.62], p = 0.005). Using a cutoff of 3%, we found that this biomarker was also associated with the development of bone metastases (HR 1.82 [95% CI 1.05-3.16], p = 0.033) and PC-specific mortality (HR 2.63 [95% CI 1.30-5.31], p = 0.004), independent of clinical parameters. BCR-free survival, bone-metastasis-free survival, and PC-specific survival were shorter for patients with higher p65 nuclear frequency (p < 0.005). As the small cores on TMAs are a limitation of the study, a backward validation of whole PC tissue section will be necessary for the implementation of p65 nuclear frequency as a PC biomarker in the clinical workflow.

Conclusions: We report the first study using the pan-Canadian multi-centre cohorts of CPCBN and validate the association between increased frequency of nuclear p65 frequency and a risk of disease progression.
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http://dx.doi.org/10.1371/journal.pmed.1002847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605640PMC
July 2019

CCN3/Nephroblastoma Overexpressed Is a Functional Mediator of Prostate Cancer Bone Metastasis That Is Associated with Poor Patient Prognosis.

Am J Pathol 2019 07 12;189(7):1451-1461. Epub 2019 Jun 12.

Goodman Cancer Research Centre, Department of Medicine, McGill University, Montréal, Québec, Canada. Electronic address:

Prostate cancer (PC) commonly metastasizes to the bone, resulting in pathologic fractures and poor prognosis. CCN3/nephroblastoma overexpressed is a secreted protein with a known role in promoting breast cancer metastasis to bone. However, in PC, CCN3 has been ascribed conflicting roles; some studies suggest that CCN3 promotes PC metastasis, whereas others argue a tumor suppressor role for CCN3 in this disease. Indeed, in the latter context, CCN3 has been shown to sequester the androgen receptor (AR) and suppress AR signaling. In the present study, we demonstrate that CCN3 functions as a bone-metastatic mediator, which is dependent on its C-terminal domain for this function. Analysis of tissue microarrays comprising >1500 primary PC patient radical prostatectomy specimens reveals that CCN3 expression correlates with aggressive disease and is negatively correlated with the expression of prostate-specific antigen, a marker of AR signaling. Together, these findings point to CCN3 as a biomarker to predict PC aggressiveness while providing clarity on its role as a functional mediator of PC bone metastasis.
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http://dx.doi.org/10.1016/j.ajpath.2019.04.006DOI Listing
July 2019

Afadin cooperates with Claudin-2 to promote breast cancer metastasis.

Genes Dev 2019 02 28;33(3-4):180-193. Epub 2019 Jan 28.

Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that the PDZ-binding motif of Claudin-2 is necessary for anchorage-independent growth of cancer cells and is required for liver metastasis. Several PDZ domain-containing proteins were identified that interact with the PDZ-binding motif of Claudin-2 in liver metastatic breast cancer cells, including Afadin, Arhgap21, Pdlim2, Pdlim7, Rims2, Scrib, and ZO-1. We specifically examined the role of Afadin as a potential Claudin-2-interacting partner that promotes breast cancer liver metastasis. Afadin associates with Claudin-2, an interaction that requires the PDZ-binding motif of Claudin-2. Loss of Afadin also impairs the ability of breast cancer cells to form colonies in soft agar and metastasize to the lungs or liver. Immunohistochemical analysis of Claudin-2 and/or Afadin expression in 206 metastatic breast cancer tumors revealed that high levels of both Claudin-2 and Afadin in primary tumors were associated with poor disease-specific survival, relapse-free survival, lung-specific relapse, and liver-specific relapse. Our findings indicate that signaling downstream from a Claudin-2/Afadin complex enables the efficient formation of breast cancer metastases. Moreover, combining Claudin-2 and Afadin as prognostic markers better predicts the potential of breast cancer to metastasize to soft tissues.
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http://dx.doi.org/10.1101/gad.319194.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362814PMC
February 2019

Identification of the Transcription Factor Relationships Associated with Androgen Deprivation Therapy Response and Metastatic Progression in Prostate Cancer.

Cancers (Basel) 2018 Oct 11;10(10). Epub 2018 Oct 11.

Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta 30322, Georgia.

Background: Patients with locally advanced or recurrent prostate cancer typically undergo androgen deprivation therapy (ADT), but the benefits are often short-lived and the responses variable. ADT failure results in castration-resistant prostate cancer (CRPC), which inevitably leads to metastasis. We hypothesized that differences in tumor transcriptional programs may reflect differential responses to ADT and subsequent metastasis.

Results: We performed whole transcriptome analysis of 20 patient-matched Pre-ADT biopsies and 20 Post-ADT prostatectomy specimens, and identified two subgroups of patients (high impact and low impact groups) that exhibited distinct transcriptional changes in response to ADT. We found that all patients lost the AR-dependent subtype (PCS2) transcriptional signatures. The high impact group maintained the more aggressive subtype (PCS1) signal, while the low impact group more resembled an AR-suppressed (PCS3) subtype. Computational analyses identified transcription factor coordinated groups (TFCGs) enriched in the high impact group network. Leveraging a large public dataset of over 800 metastatic and primary samples, we identified 33 TFCGs in common between the high impact group and metastatic lesions, including SOX4/FOXA2/GATA4, and a TFCG containing JUN, JUNB, JUND, FOS, FOSB, and FOSL1. The majority of metastatic TFCGs were subsets of larger TFCGs in the high impact group network, suggesting a refinement of critical TFCGs in prostate cancer progression.

Conclusions: We have identified TFCGs associated with pronounced initial transcriptional response to ADT, aggressive signatures, and metastasis. Our findings suggest multiple new hypotheses that could lead to novel combination therapies to prevent the development of CRPC following ADT.
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http://dx.doi.org/10.3390/cancers10100379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210624PMC
October 2018

The Terry Fox Research Institute Canadian Prostate Cancer Biomarker Network: an analysis of a pan-Canadian multi-center cohort for biomarker validation.

BMC Urol 2018 Sep 10;18(1):78. Epub 2018 Sep 10.

Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, 900, St-Denis St, room R10-464, Montréal, Québec, H2X 0A9, Canada.

Background: Refinement of parameters defining prostate cancer (PC) prognosis are urgently needed to identify patients with indolent versus aggressive disease. The Canadian Prostate Cancer Biomaker Network (CPCBN) consists of researchers from four Canadian provinces to create a validation cohort to address issues dealing with PC diagnosis and management.

Methods: A total of 1512 radical prostatectomy (RP) specimens from five different biorepositories affiliated with teaching hospitals were selected to constitute the cohort. Tumoral and adjacent benign tissues were arrayed on tissue microarrays (TMAs). A patient clinical database was developed and includes data on diagnosis, treatment and clinical outcome.

Results: Mean age at diagnosis of patients in the cohort was 61 years. Of these patients, 31% had a low grade (≤6) Gleason score (GS), 55% had GS 7 (40% of 3 + 4 and 15% of 4 + 3) and 14% had high GS (≥8) PC. The median follow-up of the cohort was 113 months. A total of 34% had a biochemical relapse, 4% developed bone metastasis and 3% of patients died from PC while 9% died of other causes. Pathological review of the TMAs confirmed the presence of tumor and benign tissue cores for > 94% of patients. Immunohistochemistry and FISH analyses, performed on a small set of specimens, showed high quality results and no biorepository-specific bias.

Conclusions: The CPCBN RP cohort is representative of real world PC disease observed in the Canadian population. The frequency of biochemical relapse and bone metastasis as events allows for a precise assessment of the prognostic value of biomarkers. This resource is available, in a step-wise manner, for researchers who intend to validate prognostic biomarkers in PC. Combining multiple biomarkers with clinical and pathologic parameters that are predictive of outcome will aid in clinical decision-making for patients treated for PC.
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http://dx.doi.org/10.1186/s12894-018-0392-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131811PMC
September 2018

Describing perspectives of health care professionals on active surveillance for the management of prostate cancer.

BMC Health Serv Res 2018 06 8;18(1):430. Epub 2018 Jun 8.

Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, 900, St Denis St, Montréal, QC, Canada.

Background: Over the last decade, active surveillance has proven to be a safe approach for patients with low-risk prostate cancer. Although active surveillance presents several advantages for both patients and the health care system, all eligible patients do not adopt this approach. Our goal was to evaluate the factors that influence physicians to recommend active surveillance and the barriers that impact adherence to this approach.

Methods: Focus groups (n = 5) were held with physicians who provided care for men with low-risk prostate cancer and had engaged in conversations with men and their families about active surveillance. The experience of health care professionals (HCPs) was captured to understand their decisions in proposing active surveillance and to reveal the barriers and facilitators that affect the adherence to this approach. A content analysis was performed on the verbatim transcripts from the sessions.

Results: Although physicians agreed that active surveillance is a suitable approach for low-risk prostate cancer patients, they were concerned about the rapidly evolving and non-standardized guidelines for patient follow-up. They pointed out the need for additional tools to appropriately identify proper patients for whom active surveillance is the best option. Urologists and radiation-oncologists were keen to collaborate with each other, but the role of general practitioner remained controversial once patients were referred to a specialist.

Conclusions: Integration of more reliable tools and/or markers in addition to more specific guidelines for patient follow-up would increase the confidence of both patients and physicians in the choice of active surveillance.
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http://dx.doi.org/10.1186/s12913-018-3273-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994022PMC
June 2018

A Multi-Institutional Validation of Gleason Score Derived from Tissue Microarray Cores.

Pathol Oncol Res 2019 Jul 6;25(3):979-986. Epub 2018 Apr 6.

Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada.

To test the agreement between high-grade PCa at RP and TMA, and the ability of TMA to predict BCR. Validation of concordance between tissue microarray (TMA) and radical prostatectomy (RP) high-grade prostate cancer (PCa) is crucial because latter determines the treated natural history of PCa. We hypothesized that TMA Gleason score is in agreement with RP pathology and capable of accurately predicting biochemical recurrence (BCR). Data were provided from a multi-institutional Canadian sample of 1333 TMA and RP specimens with complete clinicopathological data. First, rate of agreement between TMA and high-grade Gleason at RP or biopsy and RP was tested. Second, ability of RP, TMA and biopsy to predict BCR was compared. Multivariable (MVA) Cox regression models were fitted and BCR rates were illustrated with Kaplan-Meier plots. Agreement between RP and TMA and between RP and biopsy was 72.6% (95% CI:69.7-75.5) and 60.4% (95% CI:57.2-63.6), respectively. In MVA predicting BCR, the accuracy for RP, TMA and biopsy was 0.73, 0.72 and 0.68, respectively. TMA added discriminatory ability among exclusively low-grade Gleason RP patients (p = 0.02), but did not improve BCR discrimination in exclusive high-grade PCa RP patients (p = 0.8). TMA Gleason grade accurately reflects presence of high-grade Gleason in RP specimen, accurately predicts BCR rates after RP and improves prediction of BCR in low-grade Gleason patients at RP.
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http://dx.doi.org/10.1007/s12253-018-0408-6DOI Listing
July 2019

Integrin-uPAR signaling leads to FRA-1 phosphorylation and enhanced breast cancer invasion.

Breast Cancer Res 2018 01 30;20(1). Epub 2018 Jan 30.

Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.

Background: The Fos-related antigen 1 (FRA-1) transcription factor promotes tumor cell growth, invasion and metastasis. Phosphorylation of FRA-1 increases protein stability and function. We identify a novel signaling axis that leads to increased phosphorylation of FRA-1, increased extracellular matrix (ECM)-induced breast cancer cell invasion and is prognostic of poor outcome in patients with breast cancer.

Methods: While characterizing five breast cancer cell lines derived from primary human breast tumors, we identified BRC-31 as a novel basal-like cell model that expresses elevated FRA-1 levels. We interrogated the functional contribution of FRA-1 and an upstream signaling axis in breast cancer cell invasion. We extended this analysis to determine the prognostic significance of this signaling axis in samples derived from patients with breast cancer.

Results: BRC-31 cells display elevated focal adhesion kinase (FAK), SRC and extracellular signal-regulated (ERK2) phosphorylation relative to luminal breast cancer models. Inhibition of this signaling axis, with pharmacological inhibitors, reduces the phosphorylation and stabilization of FRA-1. Elevated integrin αβ and uPAR expression in these cells suggested that integrin receptors might activate this FAK-SRC-ERK2 signaling. Transient knockdown of urokinase/plasminogen activator urokinase receptor (uPAR) in basal-like breast cancer cells grown on vitronectin reduces FRA-1 phosphorylation and stabilization; and uPAR and FRA-1 are required for vitronectin-induced cell invasion. In clinical samples, a molecular component signature consisting of vitronectin-uPAR-uPA-FRA-1 predicts poor overall survival in patients with breast cancer and correlates with an FRA-1 transcriptional signature.

Conclusions: We have identified a novel signaling axis that leads to phosphorylation and enhanced activity of FRA-1, a transcription factor that is emerging as an important modulator of breast cancer progression and metastasis.
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http://dx.doi.org/10.1186/s13058-018-0936-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791353PMC
January 2018

Canadian Men's perspectives about active surveillance in prostate cancer: need for guidance and resources.

BMC Urol 2017 Oct 27;17(1):98. Epub 2017 Oct 27.

Institut du cancer de Montréal and Centre de recherche du Centre hospitalier de l'Université de Montréal, 900 St Denis St, Montreal, QC, Canada.

Background: In prostate cancer, men diagnosed with low risk disease may be monitored through an active surveillance. This research explored the perspectives of men with prostate cancer regarding their decision-making process for active surveillance to identify factors that influence their decision and assist health professionals in having conversations about this option.

Methods: Focus group interviews (n = 7) were held in several Canadian cities with men (N = 52) diagnosed with prostate cancer and eligible for active surveillance. The men's viewpoints were captured regarding their understanding of active surveillance, the factors that influenced their decision, and their experience with the approach. A content and theme analysis was performed on the verbatim transcripts from the sessions.

Results: Patients described their concerns of living with their disease without intervention, but were reassured by the close monitoring under AS while avoiding harmful side effects associated with treatments. Conversations with their doctor and how AS was described were cited as key influences in their decision, in addition to availability of information on treatment options, distrust in the health system, personality, experiences and opinions of others, and personal perspectives on quality of life.

Conclusions: Men require a thorough explanation on AS as a safe and valid option, as well as guidance towards supportive resources in their decision-making.
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http://dx.doi.org/10.1186/s12894-017-0290-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658971PMC
October 2017

Practices for Alleviating Heat Stress of Dairy Cows in Humid Continental Climates: A Literature Review.

Animals (Basel) 2017 May 2;7(5). Epub 2017 May 2.

Département des sciences animales, Université Laval, 2425 rue de l'Agriculture, Québec City, QC G1V 0A6, Canada.

Heat stress negatively affects the health and performance of dairy cows, resulting in considerable economic losses for the industry. In future years, climate change will exacerbate these losses by making the climate warmer. Physical modification of the environment is considered to be the primary means of reducing adverse effects of hot weather conditions. At present, to reduce stressful heat exposure and to cool cows, dairy farms rely on shade screens and various forms of forced convection and evaporative cooling that may include fans and misters, feed-line sprinklers, and tunnel- or cross-ventilated buildings. However, these systems have been mainly tested in subtropical areas and thus their efficiency in humid continental climates, such as in the province of Québec, Canada, is unclear. Therefore, this study reviewed the available cooling applications and assessed their potential for northern regions. Thermal stress indices such as the temperature-humidity index (THI) were used to evaluate the different cooling strategies.
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http://dx.doi.org/10.3390/ani7050037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447919PMC
May 2017

A comparative study of radical prostatectomy and permanent seed brachytherapy for low- and intermediate-risk prostate cancer.

Can Urol Assoc J 2016 Aug;10(7-8):246-250

Department of Surgery, Division of Urology, Centre hospitalier de l'Université de Montréal, Hôpital Saint-Luc, Montreal, QC, Canada.

Introduction: We sought to compare the outcomes between radical prostatectomy (RP) and permanent seed prostate brachytherapy (PB) in patients with low- and low-intermediate-risk prostate cancer from a single tertiary care centre.

Methods: Patients were selected from our institute's internal database based on preoperative selection criteria from the National Comprehensive Cancer Network (NCCN) guidelines (2015) for low- and intermediate-risk patients. No patient had received any neo-adjuvant androgen-deprivation therapy. The endpoint was biochemical recurrence (BCR) or any salvage treatment for both RP and PB at 48 ± 4 months after treatment. The biochemical relapse threshold was set at prostate-specific antigen (PSA) ≥0.5 ng/mL for PB and two PSA values of ≥0.2 ng/mL for RP. Patients from both treatment groups were compared using non-parametric tests. A binary logistic regression analysis was performed to determine an association of treatment and pretreatment factors with a BCR at 48 months.

Results: A total of 575 patients were included in this study; 254 were treated with RP and 321 with PB. BCR was not different between both groups (p=0.84, Chi-square test), and occurred in 21.2% of patients treated with RP and in 20.6% with PB. Based on univariate and multivariate logistic regression analyses, younger age, higher percentage of positive biopsies, and initial PSA were predictive of BCR. Treatment modality was not predictive in either univariate (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.64-1.44; p=0.84) or multivariate (OR 1.43, 95% CI 0.89-2.30; p=0.14) analyses.

Conclusions: Using closely related cutoff values for BCR, both RP and PB did not have significantly different outcomes at four years post-treatment. A longer followup may be necessary to detect a difference between treatments.
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http://dx.doi.org/10.5489/cuaj.3537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110416PMC
August 2016

Biopsy Based Proteomic Assay Predicts Risk of Biochemical Recurrence after Radical Prostatectomy.

J Urol 2017 04 8;197(4):1034-1040. Epub 2016 Oct 8.

Metamark Genetics, Inc., Cambridge, Massachusetts.

Purpose: Current clinicopathological parameters are insufficient to predict the likelihood of biochemical recurrence in patients with prostate cancer after radical prostatectomy. Such information may help identify patients who would likely benefit from adjuvant radiotherapy rather than active surveillance. A multiplex proteomic assay, previously tested on biopsies and found to be predictive of favorable or unfavorable pathology at radical prostatectomy, was assessed for its predictive value to identify patients at higher risk for biochemical relapse.

Materials And Methods: Proteomic assays from core needle biopsies of 288 men who subsequently underwent radical prostatectomy at CHUM (Centre hospitalier de l'Université de Montréal) were evaluated for the prediction of subsequent biochemical recurrence.

Results: Of the 288 men, biochemical relapse was observed in 47 (16.3%) and metastases were found in 5 (1.7%). Median followup was 68.5 months. The proteomic assay clearly separated patients into 3 categories, including those at low, intermediate and high risk for biochemical relapse (p = 0.0007). Assay scores predicted biochemical relapse on univariate analysis (HR 1.724, p = 0.0002 per 20% change in score), significantly better than other preoperative prognostic parameters. Additionally, the assay score had a significantly higher p value when combined with clinical National Comprehensive Cancer Network® stage compared to stage alone (HR 1.579, p = 0.0017 per 20% change in score).

Conclusions: A protein based assay score derived from diagnostic needle biopsy has strong predictive ability for biochemical relapse after surgery. These results suggest that this assay score can be used at the diagnostic stage to identify patients in whom prostate cancer is potentially more biologically aggressive and active treatment should be considered.
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http://dx.doi.org/10.1016/j.juro.2016.09.116DOI Listing
April 2017

Analysis of active surveillance uptake for low-risk localized prostate cancer in Canada: a Canadian multi-institutional study.

World J Urol 2017 Apr 22;35(4):595-603. Epub 2016 Jul 22.

Centre hospitalier de l'Université de Montréal (CHUM), Montreal, QC, Canada.

Purpose: Although the uptake of active surveillance (AS) appears to be increasing in published series, the uptake in most geographic regions remains largely unknown. Our aim was to examine practice patterns around the use of AS in low-risk prostate cancer in Canada. In addition, we examined regional variations in AS uptake, predictors of AS uptake, and persistent use for 12 months.

Methods: This is a retrospective multicentre review of low-risk patients who underwent a prostate biopsy in 2010 in six centres in four provinces (BC, QC, MB and ON). AS was identified based on chart review and required a minimum of 6 months of follow-up after diagnosis without any active treatment.

Results: Of 986 patients, 781 patients (mean age 64 years) were incident cases and over three-quarters (77.3 %) chose AS at diagnosis. There were significant differences in uptake of AS by centre (range 65.0-98.0 %, p ≤ 0.05). Key multivariate predictors of pursuing AS included older age (OR 1.34, p = 0.044), centre (p = 0.021), lower number of cores (OR 1.09, p = 0.025), lower number of positive biopsy cores (OR 0.52, p < 0.001), and lower percent core involvement (OR 0.84, p < 0.001). In total, 516 (85.4 %) men remained on AS over 12 months. Maintenance with AS over 12 months differed by centre, ranging from 64.1 to 93.9 % (p = 0.001). Predictors of maintenance with AS over 12 months included older age, centre, and lower number of positive cores.

Conclusions: Active surveillance is widely practiced across Canada, but important regional differences were observed. Further analyses are required to understand the root causes of differences and to determine whether AS uptake is changing over time.
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http://dx.doi.org/10.1007/s00345-016-1897-0DOI Listing
April 2017

The ARID1A pathway in ovarian clear cell and endometrioid carcinoma, contiguous endometriosis, and benign endometriosis.

Int J Gynaecol Obstet 2015 Jul 11;130(1):27-30. Epub 2015 Apr 11.

Centre de Recherche du Centre hospitalier de l'Université de Montréal and the Institut du Cancer de Montréal, Montréal, QC, Canada; Department of Medicine, Université de Montréal, Montréal, QC, Canada.

Objective: To assess ARID1A-encoded protein (BAF250a) and phosphorylated AKT (pAKT) expression, apoptosis, and the DNA damage response pathway in endometrioid and clear cell ovarian cancers (endometriosis-associated ovarian cancers [EAOCs]), and benign endometriotic ovarian cysts.

Methods: In a retrospective study, tissue samples were reviewed from patients who had undergone surgery for EAOC or endometriotic ovarian cysts at a center in Montreal, QC, Canada, between 2000 and 2012. A tissue microarray including cases of endometrioid carcinoma, clear cell carcinoma, contiguous endometriosis (i.e. apparently benign endometriosis near the EAOC), and benign endometriotic ovarian cysts, was analyzed for the expression of various proteins.

Results: Loss of BAF250a expression was seen in 13 (22%) of 59 endometrioid cancers, 17 (47%) of 36 clear cell cases, 8 (44%) of 18 contiguous endometriosis cases, and 3 (8%) of 66 benign endometriotic ovarian cysts. In tissues showing loss of BAF250a, expression of pAKT, γH2AX, BIM, and BAX was higher in EAOC and contiguous endometriosis than in benign endometriosis (P<0.05), whereas expression of pATM, pCHK2, and Bcl2 was low. All proteins except for Bcl2 showed low expression in benign endometriosis.

Conclusion: Loss of ARID1A-encoded protein seems to be an early event in EOAC, along with pAKT activation, alteration of γH2AX, and concomitant activation of the apoptosis pathway.
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http://dx.doi.org/10.1016/j.ijgo.2015.02.021DOI Listing
July 2015

Granulocytic immune infiltrates are essential for the efficient formation of breast cancer liver metastases.

Breast Cancer Res 2015 Mar 27;17:45. Epub 2015 Mar 27.

Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 513, Montréal, QC, H3A 1A3, Canada.

Introduction: Breast cancer cells display preferences for specific metastatic sites including the bone, lung and liver. Metastasis is a complex process that relies, in part, on interactions between disseminated cancer cells and resident/infiltrating stromal cells that constitute the metastatic microenvironment. Distinct immune infiltrates can either impair the metastatic process or conversely, assist in the seeding, colonization and growth of disseminated cancer cells.

Methods: Using in vivo selection approaches, we previously isolated 4T1-derived breast cancer cells that preferentially metastasize to these organs and tissues. In this study, we examined whether the propensity of breast cancer cells to metastasize to the lung, liver or bone is associated with and dependent on distinct patterns of immune cell infiltration. Immunohistocytochemistry and immunohistofluorescence approaches were used to quantify innate immune cell infiltrates within distinct metastases and depletion of Gr1+ (Ly-6C and Ly-6G) or specifically Ly-6G+ cells was performed to functionally interrogate the role of Ly-6G+ infiltrates in promoting metastasis to these organs.

Results: We show that T lymphocytes (CD3+), myeloid-derived (Gr-1+) cells and neutrophils (Ly-6G+ or NE+) exhibit the most pronounced recruitment in lung and liver metastases, with markedly less recruitment within bone metastatic lesions. Interestingly, these infiltrating cell populations display different patterns of localization within soft tissue metastases. T lymphocytes and granulocytic immune infiltrates are localized around the periphery of liver metastases whereas they were dispersed throughout the lung metastases. Furthermore, Gr-1+ cell-depletion studies demonstrate that infiltrating myeloid-derived cells are essential for the formation of breast cancer liver metastases but dispensable for metastasis to the lung and bone. A specific role for the granulocytic component of the innate immune infiltrate was revealed through Ly-6G+ cell-depletion experiments, which resulted in significantly impaired formation of liver metastases. Finally, we demonstrate that the CD11b+/Ly-6G+ neutrophils that infiltrate and surround the liver metastases are polarized toward an N2 phenotype, which have previously been shown to enhance tumor growth and metastasis.

Conclusions: Our results demonstrate that the liver-metastatic potential of breast cancer cells is heavily reliant on interactions with infiltrating Ly-6G+ cells within the liver microenvironment.
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http://dx.doi.org/10.1186/s13058-015-0558-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413545PMC
March 2015

DNA damage signaling and apoptosis in preinvasive tubal lesions of ovarian carcinoma.

Int J Gynecol Cancer 2015 Jun;25(5):761-9

*Centre de Recherche du Centre hospitalier de l'Université de Montréal; †Institut du Cancer de Montréal, Montreal, Quebec, Canada; ‡Department of Gynecology, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; Departments of §Pathology, and ∥Gynecology, Centre hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.

Objective: High-grade serous ovarian cancer (HGSC) is the most life-threatening gynecological malignancy despite surgery and chemotherapy. A better understanding of the molecular basis of the preinvasive stages might be helpful in early detection and diagnosis. Genetic instability is 1 of the characteristics shared by most human cancers, and its level is variable through precancerous lesions to advanced cancer. Because DNA damage response (DDR) has been described as 1 of the first phases in genomic instability, we investigated the level of DDR activation and the apoptosis pathway in serous tubal intraepithelial carcinoma (STIC), the potential precursor of HGSC.

Methods/materials: A tissue microarray including 21 benign fallopian tubes, 21 STICs, 17 HGSCs from patients with STICs (associated ovarian cancer [AOC]) from the same individuals, and 30 HGSCs without STICs (non-AOC) was used in this study.Immunohistochemistry was performed to evaluate the level of DDR proteins (pATM, pChk2, γH2AX, 53BP1, and TRF2), apoptosis proteins (Bcl2, BAX, and BIM), and cyclin E.

Results: The expression of all DDR proteins increased from benign fallopian tubes to STICs. The level of expression of pATM, pChk2, γH2AX, and TRF2 was also increased in STICs in comparison with AOC. BAX, BIM, and cyclin E expressions were high in STICs, whereas Bcl2 expression was low. Immunohistochemical profiles of AOC and non-AOC were also different.

Conclusions: These results suggest an activation of the DDR and apoptosis pathways in STICs, indicating that genomic instability may occur early in the precancerous lesions of HGSC.
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http://dx.doi.org/10.1097/IGC.0000000000000196DOI Listing
June 2015

ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone.

Breast Cancer Res 2012 Nov 22;14(6):R149. Epub 2012 Nov 22.

Introduction: Bone is the most common site of breast cancer metastasis, and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases.

Methods: To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene-expression profiles from laser-capture microdissected trephine biopsies of both breast cancer bone metastases and independent primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared with primary, bone-metastatic breast tumors.

Results: ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary breast tumors. In addition, ABCC5 was significantly upregulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 substantially reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers in vivo. Finally, conditioned media from breast cancer cells with reduced ABCC5 expression failed to induce in vitro osteoclastogenesis to the same extent as conditioned media from breast cancer cells expressing ABCC5.

Conclusions: Our data suggest that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for efficient osteoclast-mediated bone resorption. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis.
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http://dx.doi.org/10.1186/bcr3361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053136PMC
November 2012

CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis.

J Cell Commun Signal 2012 Jun 18;6(2):73-85. Epub 2012 Mar 18.

Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 513, Montreal, Quebec, Canada, H3A 1A3.

The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity. These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease. In this review, we focus on CCN3, a founding member of this family, and its role in regulating cells within the bone microenvironment. CCN3 impairs normal osteoblast differentiation through multiple mechanisms, which include the neutralization of pro-osteoblastogenic stimuli such as BMP and Wnt family signals or the activation of pathways that suppress osteoblastogenesis, such as Notch. In contrast, CCN3 is known to promote chondrocyte differentiation. Given these functions, it is not surprising that CCN3 has been implicated in the progression of primary bone cancers such as osteosarcoma, Ewing's sarcoma and chondrosarcoma. More recently, emerging evidence suggests that CCN3 may also influence the ability of metastatic cancers to colonize and grow in bone.
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http://dx.doi.org/10.1007/s12079-012-0161-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368020PMC
June 2012

Necdin, a p53-target gene, is an inhibitor of p53-mediated growth arrest.

PLoS One 2012 15;7(2):e31916. Epub 2012 Feb 15.

Centre de recherche du Centre hospitalier de l'Université de Montréal and Institut du cancer de Montréal, Montréal, Québec, Canada.

In vitro, cellular immortalization and transformation define a model for multistep carcinogenesis and current ongoing challenges include the identification of specific molecular events associated with steps along this oncogenic pathway. Here, using NIH3T3 cells, we identified transcriptionally related events associated with the expression of Polyomavirus Large-T antigen (PyLT), a potent viral oncogene. We propose that a subset of these alterations in gene expression may be related to the early events that contribute to carcinogenesis. The proposed tumor suppressor Necdin, known to be regulated by p53, was within a group of genes that was consistently upregulated in the presence of PyLT. While Necdin is induced following p53 activation with different genotoxic stresses, Necdin induction by PyLT did not involve p53 activation or the Rb-binding site of PyLT. Necdin depletion by shRNA conferred a proliferative advantage to NIH3T3 and PyLT-expressing NIH3T3 (NIHLT) cells. In contrast, our results demonstrate that although overexpression of Necdin induced a growth arrest in NIH3T3 and NIHLT cells, a growing population rapidly emerged from these arrested cells. This population no longer showed significant proliferation defects despite high Necdin expression. Moreover, we established that Necdin is a negative regulator of p53-mediated growth arrest induced by nutlin-3, suggesting that Necdin upregulation could contribute to the bypass of a p53-response in p53 wild type tumors. To support this, we characterized Necdin expression in low malignant potential ovarian cancer (LMP) where p53 mutations rarely occur. Elevated levels of Necdin expression were observed in LMP when compared to aggressive serous ovarian cancers. We propose that in some contexts, the constitutive expression of Necdin could contribute to cancer promotion by delaying appropriate p53 responses and potentially promote genomic instability.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031916PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280226PMC
June 2012

Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans.

J Clin Invest 2012 Feb 24;122(2):545-52. Epub 2012 Jan 24.

Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Quebec City, Quebec, Canada.

Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.
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http://dx.doi.org/10.1172/JCI60433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266793PMC
February 2012

CCN3 impairs osteoblast and stimulates osteoclast differentiation to favor breast cancer metastasis to bone.

Am J Pathol 2011 May;178(5):2377-88

Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.

Bone is a preferred site for breast cancer metastasis, causing pain, fractures, spinal cord compressions, and hypercalcemia, all of which can significantly diminish the patient's quality of life. We identified CCN3 as a novel factor that is highly expressed in bone metastatic breast cancer cells from a xenograft mouse model and in bone metastatic lesions from patients with breast cancer. We demonstrate that CCN3 overexpression enhances the ability of weakly bone metastatic breast cancer cells to colonize and grow in the bone without altering their growth in the mammary fat pad. We further demonstrated that human recombinant CCN3 inhibits osteoblast differentiation from primary bone marrow cultures, leading to a higher receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) ratio. In conjunction with its ability to impair osteoblast differentiation, we uncovered a novel role for CCN3 in promoting osteoclast differentiation from RANKL-primed monocyte precursors. CCN3 exerts its pro-osteoclastogenic effects by promoting calcium oscillations and nuclear factor of activated T cells c1 (NFATc1) nuclear translocation. Together, these results demonstrate that CCN3 regulates the differentiation of bone resident cells to create a resorptive environment that promotes the formation of osteolytic breast cancer metastases.
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http://dx.doi.org/10.1016/j.ajpath.2011.01.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081179PMC
May 2011
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