TIMP-1 is an activator of MHC-I expression in myeloid dendritic cells with implications for tumor immunogenicity.

Immune checkpoint therapies (ICT) for advanced solid tumors mark a new milestone in cancer therapy. Yet their efficacy is often limited by poor immunogenicity, attributed to inadequate priming and generation of antitumor T cells by dendritic cells (DCs). Identifying biomarkers to enhance DC functions in such tumors is thus crucial. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1), recognized for its influence on immune cells, has an underexplored relationship with DCs. Our research reveals a correlation between high TIMP1 levels in metastatic melanoma and increased CD8 + T cell infiltration and survival. Network studies indicate a functional connection with HLA genes. Spatial transcriptomic analysis of a national melanoma cohort revealed that TIMP1 expression in immune compartments associates with an HLA-A/MHC-I peptide loading signature in lymph nodes. Primary human and bone-marrow-derived DCs secrete TIMP-1, which notably increases MHC-I expression in classical type 1 dendritic cells (cDC1), especially under melanoma antigen exposure. TIMP-1 affects the immunoproteasome/TAP complex, as seen by upregulated PSMB8 and TAP-1 levels of myeloid DCs. This study uncovers the role of TIMP-1 in DC-mediated immunogenicity with insights into CD8 + T cell activation, providing a foundation for mechanistic exploration and highlighting its potential as a new target for combinatorial immunotherapy to enhance ICT effectiveness.

Effect of caldesmon mutations in the development of zebrafish embryos.

Cancer is a profound medical concern and better treatments are needed for cancer patients. Therefore, new cancer targets are constantly being studied. These targets need not only be relevant for cancer progression, but their modulation needs to be tolerated reasonably well by the host. Caldesmon is one of these proposed novel targets for cancer therapy. Therefore, we analyzed effects of caldesmon mutations in normal development using genetically modified zebrafish embryos. We analyzed mutations in both zebrafish caldesmon genes, cald1a and cald1b and analyzed effects of either mutation alone or as in combination in double homozygous embryos using molecular, morphological and functional analyses. The effects of caldesmon mutations were mild and the gross development of zebrafish embryos was normal. The caldesmon mutant embryos had, however, alterations in response to light-stimulus in behavioural assays. Taken together, the effects of caldesmon mutations in the development of zebrafish embryos were reasonably well tolerated and did not indicate significant concerns for caldesmon being a potential target for cancer therapy.

Role of Ubiquitin and SUMO in Intracellular Trafficking.

Precise location of proteins at a given time within a cell is essential to convey specific signals and result in a relevant functional outcome. Small ubiquitin-like modifications, such as ubiquitin and SUMO, represent a delicate and diverse way to transiently regulate intracellular trafficking events of existing proteins in cells. Trafficking of multiple proteins is controlled reversibly by ubiquitin and/or SUMO directly or indirectly via regulation of transport machinery components. Regulation is dynamic and multilayered, involving active crosstalk and interdependence between post-translational modifications. However, in most cases regulation appears very complex, and the mechanistic details regarding how ubiquitin and SUMO control protein location in cells are not yet fully understood. Moreover, most of the findings still lack in vivo evidence in multicellular organisms.

SUMOylation regulates nuclear accumulation and signaling activity of the soluble intracellular domain of the ErbB4 receptor tyrosine kinase.

Erb-B2 receptor tyrosine kinase 4 (ErbB4) is a kinase that can signal via a proteolytically released intracellular domain (ICD) in addition to classical receptor tyrosine kinase-activated signaling cascades. Previously, we have demonstrated that ErbB4 ICD is posttranslationally modified by the small ubiquitin-like modifier (SUMO) and functionally interacts with the PIAS3 SUMO E3 ligase. However, direct evidence of SUMO modification in ErbB4 signaling has remained elusive. Here, we report that the conserved lysine residue 714 in the ErbB4 ICD undergoes SUMO modification, which was reversed by sentrin-specific proteases (SENPs) 1, 2, and 5. Although ErbB4 kinase activity was not necessary for the SUMOylation, the SUMOylated ErbB4 ICD was tyrosine phosphorylated to a higher extent than unmodified ErbB4 ICD. Mutation of the SUMOylation site compromised neither ErbB4-induced phosphorylation of the canonical signaling pathway effectors Erk1/2, Akt, or STAT5 nor ErbB4 stability. In contrast, SUMOylation was required for nuclear accumulation of the ErbB4 ICD. We also found that Lys-714 was located within a leucine-rich stretch, which resembles a nuclear export signal, and could be inactivated by site-directed mutagenesis. Furthermore, SUMOylation modulated the interaction of ErbB4 with chromosomal region maintenance 1 (CRM1), the major nuclear export receptor for proteins. Finally, the SUMO acceptor lysine was functionally required for ErbB4 ICD-mediated inhibition of mammary epithelial cell differentiation in a three-dimensional cell culture model. Our findings indicate that a SUMOylation-mediated mechanism regulates nuclear localization and function of the ICD of ErbB4 receptor tyrosine kinase.

Clinical challenges in cultural psychiatry - searching for meaning, searching for methods†.

BACKGROUND: Mental health services in Sweden are confronted with globalization and refugee migration from conflict- and war-torn countries. AIM: To discuss how clinicians in Sweden can deal with a series of challenges in a changing globalized society, ranging from difficulties of overcoming barriers to help seeking to difficulties of identifying trauma and finding culturally adapted clinical tools. METHOD: Case vignettes are presented to exemplify challenges. Different approaches developed to support clinicians are presented. RESULTS: The concepts of patient centered care and shared decision-making as well as the cultural formulation interview, are recommended to explore the significance of culture and context in psychiatric assessments. Acknowledging relational aspects of care and of paying attention to the patients' social worlds in clinical work is also essential. CONCLUSIONS: The article includes recommendations for training as well as an appeal for the involvement of the wider society in the work to guarantee equitable and high-quality mental health services for some of the most vulnerable patient groups in society.

Assessment and treatment of asylum seekers after a suicide attempt: a comparative study of people registered at mental health services in a Swedish location.

BACKGROUND: Even though asylum seekers are considered vulnerable to mental ill-health, knowledge of their suicidal behaviour is limited. The aim of this study was to improve our understanding of factors that influence the clinical assessment of asylum seekers who have attempted suicide compared to the assessment of non-asylum seekers. METHODS: The study focused on 88 asylum seekers registered for suicide attempts in mental health services 2005-2009, who were matched for age and gender and compared with 88 suicide attempters with Swedish personal identity numbers. The medical records were analysed with a quantitative protocol, focusing on social risk and protective factors, health history, current clinical picture as well as the assessment procedure, diagnostics, patterns of treatment and follow-up in this clinical group. Data was analysed using the chi-square test, Fisher's exact probability test, and the Mann-Whitney U test. RESULTS: As in earlier studies, asylum seekers were more traumatized, had different social risk factors and received different diagnoses than the controls. Asylum seekers were referred to less specialized follow-up after treatment, in spite of their health history and of previous and current clinical pictures indicating a similar or--in the case of the female asylum seekers--more serious mental health condition. Female asylum seekers also received more intense and prolonged in-patient treatment than female controls. Asylum seekers appeared to have social networks more often than the control group. However, there was less documentation of the social context, previous suicidal behaviour, and on suicide in the family and close environment of the asylum-seeking men. Information on suicidal intent was lacking in a majority of both groups. The time relation of the suicide attempt and the asylum process suggested the importance of the asylum decision, as well as the possible role of earlier mental health problems and premigration stress, for the suicidal behaviour. CONCLUSIONS: The groups had different sets of risk factors and clinical pictures. There was a lack of early and thorough exploration of suicide intent for both groups, and of contextual and subjective factors for the asylum seekers. Differences in follow-up indicate unequal access to care.

Phage Biosensor for the Classification of Metastatic Urological Cancers from Urine.

Most of the annual 10 million cancer-related deaths are caused by metastatic disease. Survival rates for cancer are strongly dependent on the type of cancer and its stage at detection. Early detection remains a challenge due to the lack of reliable biomarkers and cost-efficient screening methods. Phage biosensors can offer a solution for early detection using non-invasive liquid biopsies. Here, we report the first results of the bifunctional phage biosensor to detect metastatic urological cancers from urine. A dye-sensitized phage library was used to select metastasis-related phage binders. After selection rounds, the most promising phage candidate was used to classify metastatic cancer from controls. Additionally, we applied one chemical sensor (phenoxazine non-fluorescent dye) to classify cancer from urine. A statistical significance (p = 0.0002) was observed between metastatic and non-metastatic cancer, with sensitivity of 70% and specificity of 79%. Furthermore, the chemical sensor demonstrated significance in detecting cancer (p < 0.0001) with a sensitivity of 71% and a specificity of 75%. Our data suggest a new promising field for urine biomarker research, and further evaluation with prospectively collected samples is ongoing. In conclusion, we report, for the first time, the potential of a chemical- and phage-based biosensor method to detect metastatic cancer using urine.

Protein inhibitor of activated STAT3 (PIAS3) protein promotes SUMOylation and nuclear sequestration of the intracellular domain of ErbB4 protein.

ErbB4 is a receptor tyrosine kinase implicated in the development and homeostasis of the heart, central nervous system, and mammary gland. Cleavable isoforms of ErbB4 release a soluble intracellular domain (ICD) that can translocate to the nucleus and function as a transcriptional coregulator. In search of regulatory mechanisms of ErbB4 ICD function, we identified PIAS3 as a novel interaction partner of ErbB4 ICD. In keeping with the small ubiquitin-like modifier (SUMO) E3 ligase function of protein inhibitor of activated STAT (PIAS) proteins, we showed that the ErbB4 ICD is modified by SUMO, and that PIAS3 stimulates the SUMOylation. Upon overexpression of PIAS3, the ErbB4 ICD generated from the full-length receptor accumulated into the nucleus in a manner that was dependent on the functional nuclear localization signal of ErbB4. In the nucleus, ErbB4 colocalized with PIAS3 and SUMO-1 in promyelocytic leukemia nuclear bodies, nuclear domains involved in regulation of transcription. Accordingly, PIAS3 overexpression had an effect on the transcriptional coregulatory activity of ErbB4, repressing its ability to coactivate transcription with Yes-associated protein. Finally, knockdown of PIAS3 with siRNA partially rescued the inhibitory effect of the ErbB4 ICD on differentiation of MDA-MB-468 breast cancer and HC11 mammary epithelial cells. Our findings illustrate that PIAS3 is a novel regulator of ErbB4 receptor tyrosine kinase, controlling its nuclear sequestration and function.

Radium-223 dichloride treatment in metastatic castration-resistant prostate cancer in Finland: A real-world evidence multicenter study.

BACKGROUND: Radium-233 dichloride is an alpha emitter that specifically targets bone metastases in prostate cancer. Results of a previously reported phase III randomized trial showed survival benefit for radium-223 compared to best supportive care in castration-resistant prostate cancer (CRPC) with bone metastases. However, real-world data are also needed with wider inclusion criteria. METHODS: We report results of a retrospective multicenter study including all patients with metastatic CRPC treated with radium-223 in all five university hospitals in Finland since the introduction of the treatment. We identified 160 patients who had received radium-223 in Finland in 2014-2019. RESULTS: The median overall survival (OS) was 13.8 months (range 0.5-57 months), and the median real-world progression-free survival (rwPFS) was 4.9 months (range 0.5-29.8 months). Alkaline phosphatase (ALP) values within the normal range before and during the radium-223 treatment or the reduction of elevated ALP to normal range during treatment were associated with better OS when compared to elevated ALP values before and during treatment (p < 0.0001). High prostate-specific antigen (PSA) level (≥100 µg/L) before radium-223 treatment was associated with poor OS compared to low PSA level (<20 µg/L) (p = 0.0001). Most patients (57%) experienced pain relief. Pain relief indicated better OS (p = 0.002). Radium-223 treatment was well tolerated. Toxicity was mostly low grade. Only 12.5% of the patients had grade III-IV adverse events, most commonly anemia, neutropenia, leucopenia, and thrombocytopenia. CONCLUSION: Radium-223 was well tolerated in routine clinical practice, and most patients achieved pain relief. Pain relief, ALP normalization, lower baseline PSA, and PSA decrease during radium-223 treatment were prognostic for better survival. The efficacy of radium-223 in mCRPC as estimated using OS was comparable to earlier randomized trial in this retrospective real-world study. Our results support using radium-223 for mCRPC patients with symptomatic bone metastases even in the era of new-generation androgen receptor-targeted agents.

Glucocorticoid receptor-induced non-muscle caldesmon regulates metastasis in castration-resistant prostate cancer.

Lethal prostate cancer (PCa) is characterized by the presence of metastases and development of resistance to therapies. Metastases form in a multi-step process enabled by dynamic cytoskeleton remodeling. An actin cytoskeleton regulating gene, CALD1, encodes a protein caldesmon (CaD). Its isoform, low-molecular-weight CaD (l-CaD), operates in non-muscle cells, supporting the function of filaments involved in force production and mechanosensing. Several factors, including glucocorticoid receptor (GR), have been identified as regulators of l-CaD in different cell types, but the regulation of l-CaD in PCa has not been defined. PCa develops resistance in response to therapeutic inhibition of androgen signaling by multiple strategies. Known strategies include androgen receptor (AR) alterations, modified steroid synthesis, and bypassing AR signaling, for example, by GR upregulation. Here, we report that in vitro downregulation of l-CaD promotes epithelial phenotype and reduces spheroid growth in 3D, which is reflected in vivo in reduced formation of metastases in zebrafish PCa xenografts. In accordance, CALD1 mRNA expression correlates with epithelial-to-mesenchymal transition (EMT) transcripts in PCa patients. We also show that CALD1 is highly co-expressed with GR in multiple PCa data sets, and GR activation upregulates l-CaD in vitro. Moreover, GR upregulation associates with increased l-CaD expression after the development of resistance to antiandrogen therapy in PCa xenograft mouse models. In summary, GR-regulated l-CaD plays a role in forming PCa metastases, being clinically relevant when antiandrogen resistance is attained by the means of bypassing AR signaling by GR upregulation.

TSPO is a potential independent prognostic factor associated with cellular respiration and p16 in head and neck squamous cell carcinoma.

Background: Treatment resistance and relapse are common problems in head and neck squamous cell carcinoma (HNSCC). Except for p16, no clinically accepted prognostic biomarkers are available for HNSCC. New biomarkers predictive of recurrence and survival are crucial for optimal treatment planning and patient outcome. High translocator protein (TSPO) levels have been associated with poor survival in cancer, but the role of TSPO has not been extensively evaluated in HNSCC. Materials and methods: TSPO expression was determined in a large population-based tissue microarray cohort including 611 patients with HNSCC and evaluated for survival in several clinicopathological subgroups. A TCGA HNSCC cohort was used to further analyze the role of TSPO in HNSCC. Results: TSPO expression was downregulated in more aggressive tumors. Low TSPO expression associated with worse 5-year survival and was an independent prognostic factor for disease-specific survival. Subgroup analyses showed that low TSPO expression associated with worse survival particularly in p16-positive oropharyngeal cancer. In silico analyses supported the prognostic role of TSPO. Cellular respiration had the highest significance in pathway analyses for genes expressed positively with TSPO. Conclusion: Decreased TSPO expression associates with poor prognosis in HNSCC. TSPO is a prognostic biomarker in HNSCC to potentially guide treatment stratification especially in p16-positive oropharyngeal cancer.

Isoform-specific monoubiquitination, endocytosis, and degradation of alternatively spliced ErbB4 isoforms.

Endocytosis and subsequent lysosomal degradation serve as a well characterized mechanism to fine-tune and down-regulate EGFR signaling. However, other members of the EGFR/ErbB receptor family have been reported to be endocytosis-impaired. Here we demonstrate that endocytosis of ErbB4 is regulated in an isoform-specific manner: CYT-1 isoforms were efficiently endocytosed whereas CYT-2 isoforms were endocytosis-impaired. CYT-1 isoforms in endocytic vesicles colocalized with Rab5 and Rab7 indicating trafficking via early endosomes to late endosomal/lysosomal structures. A PPXY motif within the CYT-1-specific sequence that lacks from CYT-2 was necessary both for ubiquitination and endocytosis of CYT-1 isoforms and provided a binding site for a WW domain-containing ubiquitin ligase Itch. Itch catalyzed ubiquitination of ErbB4 CYT-1, promoted its localization into intracellular vesicles, and stimulated degradation of ErbB4 CYT-1. Dominant negative Itch suppressed ErbB4 CYT-1 endocytosis and degradation. These data indicate that ErbB4 isoforms differ in endocytosis and degradation by a mechanism mediated by CYT-1-specific PPXY motif interacting with a WW domain-containing E3 ubiquitin ligase.

Safe but isolated - an interview study with Iraqi refugees in Sweden about social networks, social support, and mental health.

BACKGROUND: Problems with social networks and social support are known to be associated with mental ill-health in refugees. Social support after migration promotes resilience. AIM: To study how Iraqi refugees who arrived in Sweden after the year 2000 perceived their social networks and social support, and to relate the observed network characteristics and changes to the refugees' mental health and well-being. METHOD: Semi-structured interviews with 31 refugees, including questions on background and migration experiences, a biographical network map, and three health assessment scales. The findings were analysed with descriptive statistics and content thematic analysis. RESULTS: The respondents' networks were diminished. Social support was continued to be provided mainly by family members and supplemented by support from authorities. The main themes of the refugee experience of post-migration challenges were weakened social networks, barriers to integration and challenges to cultural and religious belonging. Failed reunion and worrying about relatives was described as particularly painful. Negative contacts with authority persons were often seen as humiliating or discriminating. Acquiring a new cultural belonging was described as challenging. At the same time, changing family and gender roles made it more difficult to preserve and develop the culture of origin. Traumatic experiences and mental health problems were common in this group. Family issues were more often than integration difficulties associated with mental health problems. CONCLUSION: In order to strengthen post-migration well-being and adaptation, authorities should support the refugees' social networks. Clinicians need to address post-migration problems and challenges, including the meaning and function of social networks.

More Than Meets the Eye: Scientific Rationale behind Molecular Imaging and Therapeutic Targeting of Prostate-Specific Membrane Antigen (PSMA) in Metastatic Prostate Cancer and Beyond.

Prostate cancer is the second most common cancer type in men globally. Although the prognosis for localized prostate cancer is good, no curative treatments are available for metastatic disease. Better diagnostic methods could help target therapies and improve the outcome. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on malignant prostate tumor cells and correlates with the aggressiveness of the disease. PSMA is a clinically validated target for positron emission tomography (PET) imaging-based diagnostics in prostate cancer, and during recent years several therapeutics have been developed based on PSMA expression and activity. The expression of PSMA in prostate cancer can be very heterogeneous and some metastases are negative for PSMA. Determinants that dictate clinical responses to PSMA-targeting therapeutics are not well known. Moreover, it is not clear how to manipulate PSMA expression for therapeutic purposes and develop rational treatment combinations. A deeper understanding of the biology behind the use of PSMA would help the development of theranostics with radiolabeled compounds and other PSMA-based therapeutic approaches. Along with PSMA several other targets have also been evaluated or are currently under investigation in preclinical or clinical settings in prostate cancer. Here we critically elaborate the biology and scientific rationale behind the use of PSMA and other targets in the detection and therapeutic targeting of metastatic prostate cancer.

Therapeutic Potential of Targeting the SUMO Pathway in Cancer.

SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

A Public Mental Health Study Among Iraqi Refugees in Sweden: Social Determinants, Resilience, Gender, and Cultural Context.

This public mental health study highlights the interactions among social determinants and resilience on mental health, PTSD and acculturation among Iraqi refugees in Sweden 2012-2013. Objectives: The study aims to understand participants' health, resilience and acculturation, paying specific attention to gender differences. Design: The study, using a convenience sampling survey design (N = 4010, 53.2% men), included measures on social determinants, general health, coping, CD-RISC, selected questions from the EMIC, PC-PTSD, and acculturation. Results: Gender differences and reported differences between life experiences in Iraq and Sweden were strong. In Sweden, religious activity was more widespread among women, whereas activity reflecting religion and spirituality as a coping mechanism decreased significantly among men. A sense of belonging both to a Swedish and an Iraqi ethnic identity was frequent. Positive self-evaluation in personal and social areas and goals in life was strong. The strongest perceived source of social support was from parents and siblings, while support from authorities generally was perceived as low. Self-rated health was high and the incidence of PTSD was low. A clear majority identified multiple social determinants contributing to mental health problems. Social or situational and emotional or developmental explanations were the most common. In general, resilience (as measured with CD-RISC) was low, with women's scores lower than that of men. Conclusions: Vulnerability manifested itself in unemployment after a long period in Sweden, weak social networks outside the family, unsupportive authorities, gender differences in acculturation, and women showing more mental health problems. Though low socially determined personal scores of resilience were found, we also identified a strong level of resilience, when using a culture-sensitive approach and appraising resilience as expressed in coping, meaning, and goals in life. Clinicians need to be aware of the risks of poorer mental health among refugees in general and women in particular, although mental health problems should not be presumed in the individual patient. Instead clinicians need to find ways of exploring the cultural and social worlds and needs of refugee patients. Authorities need to address the described post-migration problems and unmet needs of social support, together comprising the well-established area of the social determinants of health.

EGFR targeting drugs in the treatment of head and neck squamous cell carcinoma.

IMPORTANCE OF THE FIELD: Head and neck cancer is the sixth most common cancer worldwide. Despite intense efforts to improve different treatment modalities, mortality rates in advanced cases remain high. AREAS COVERED IN THE REVIEW: EGFR targeting mAb cetuximab (Erbitux) has been approved for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy and for recurrent or metastatic HNSCC. Here, we review recent scientific advances, as well as future research goals regarding EGFR inhibitors in the treatment of HNSCC. Information was compiled by searching the PubMed, Web of Knowledge and American Society of Clinical Oncology databases for articles published before October 2009. The search terms included 'head and neck cancer', 'EGFR', 'cetuximab', 'panitumumab', 'zalutumumab', 'nimotuzumab', 'erlotinib', 'gefitinib' and 'lapatinib'. The National Institutes of Health registry of clinical trials ( www.clinicaltrials.gov ) was used to search for clinical trials in HNSCC. WHAT THE READER WILL GAIN: The background scientific rationale, clinical efficacy and development of EGFR inhibitors in HNSCC are discussed. TAKE HOME MESSAGE: Cetuximab significantly improves survival of patients with locally advanced or metastatic HNSCC. Treatment strategies combining EGFR inhibitors with multimodality approaches may eventually increase cure rate in HNSCC.

Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth.

The ErbB1 and ErbB2 receptors are oncogenes with therapeutic significance in human cancer, whereas the transforming potential of the related ErbB4 receptor has remained controversial. Here, we have addressed whether four alternatively spliced ErbB4 isoforms differ in regulating cellular responses relevant for tumor growth. We show that the two tumor necrosis factor-alpha converting enzyme (TACE)-cleavable ErbB4 isoforms (the juxtamembrane [JM]-a isoforms) were overexpressed in a subset of primary human breast cancers together with TACE. The overexpression of the JM-a cytoplasmic (CYT)-2 ErbB4 isoform promoted ErbB4 phosphorylation, survival of interleukin-3-dependent cells, and proliferation of breast cancer cells even in the absence of ligand stimulation, whereas activation of the other three ErbB4 isoforms required ligand stimulation. Ligand-independent cellular responses to ErbB4 JM-a CYT-2 overexpression were regulated by both tyrosine kinase activity and a two-step proteolytic generation of an intracellular receptor fragment involving first a TACE-like proteinase, followed by gamma-secretase activity. These data suggest a novel transforming mechanism for the ErbB4 receptor in human breast cancer that is 1) specific for a single receptor isoform and 2) depends on proteinase cleavage and kinase activity but not ligand activation of the receptor.

Association of Wwox with ErbB4 in breast cancer.

WWOX, WW domain-containing oxidoreductase, is a tumor suppressor that is altered in many human cancers, including breast cancer. Wwox interacts with the ErbB4 receptor, reduces nuclear translocation of the cleaved intracellular domain of ErbB4, and inhibits its transactivation function mediated through Yes-associated protein. Here, we assessed the clinical significance of the Wwox-ErbB4 association. We determined Wwox protein expression by immunohistochemistry in a series of 556 breast cancers. Wwox expression was absent in 36% of the cancers, and loss of Wwox expression was associated with unfavorable outcome (P = 0.02). Membranous location of ErbB4 was associated with favorable survival compared with women whose cancer lacked such ErbB4 expression (P = 0.02). Wwox expression was strongly associated with membranous ErbB4 localization (P = 0.0003) and with overall ErbB4 expression (P = 0.0002). Coexpression of membranous ErbB4 and Wwox was associated with favorable outcome compared with cases with membranous ErbB4 and no Wwox immunoreactivity (P = 0.002). In vitro, Wwox associated with the two ErbB4 isoforms, JM-a CYT-1 and JM-a CYT-2, expressed in breast cancer. Moreover, expression of Wwox both in vitro and in vivo led to accumulation of total full-length membrane-associated ErbB4. These results suggest that expression of Wwox is associated with ErbB4 expression and that their coexpression has prognostic significance in breast cancer.

PARP Inhibitors in Prostate Cancer­The Preclinical Rationale and Current Clinical Development.

Prostate cancer is globally the second most commonly diagnosed cancer type in men. Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms of prostate cancer and castration resistance. Prostate cancer with DNA repair defects may be vulnerable to therapeutic targeting by Poly(ADP-ribose) polymerase (PARP) inhibitors. PARP enzymes modify target proteins with ADP-ribose in a process called PARylation and are in particular involved in single strand break repair. The rationale behind the clinical trials that led to the current use of PARP inhibitors to treat cancer was to target the dependence of BRCA-mutant cancer cells on the PARP-associated repair pathway due to deficiency in homologous recombination. However, recent studies have proposed therapeutic potential for PARP inhibitors in tumors with a variety of vulnerabilities generating dependence on PARP beyond the synthetic lethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initially thought. Importantly, PARP-associated DNA repair pathways are also closely connected to androgen receptor (AR) signaling, which is a key regulator of tumor growth and a central therapeutic target in prostate cancer. In this review, we provide an extensive overview of published and ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss the underlying biology. Several clinical trials are currently studying PARP inhibitor mono- and combination therapies in the treatment of prostate cancer. Integration of drugs targeting DNA repair pathways in prostate cancer treatment modalities allows developing of more personalized care taking also into account the genetic makeup of individual tumors.