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PubMed2001

Men's attitudes toward prostate cancer and seeking prostate-specific antigen testing.

BACKGROUND: Although the Australian Cancer Society recommends against performing PSA tests to screen for prostate cancer, many Australian men currently undergo such screening. This study investigated attitudinal variables that may predict prostate cancer screening behaviors in this context. METHODS: A questionnaire was administered by mail in a two-phase procedure, first to a sample of 1,461 men (46% response), then to 919 men from the initial sample. Prostate cancer screening behaviors of men > 40 years old were examined. The questionnaire assessed worry about prostate cancer, perceived vulnerability to prostate cancer, belief in the efficacy of PSA testing for detection, having received a PSA test for detection, and the presence of urologic symptoms at the time of testing. RESULTS: Men who had had PSA testing with urologic symptoms at the time of the test were more worried about prostate cancer and perceived themselves as more vulnerable to prostate cancer compared with both asymptomatic tested and untested men. Men who had undergone PSA testing believed the test to be more effective in the detection of prostate cancer than did men who had not. CONCLUSIONS: Urologic symptoms act as a risk cue for men to prostate cancer. Asymptomatic men should be considered separately from symptomatic men in the investigation of psychological variables predictive of seeking screening for prostate cancer. These findings are discussed in terms of both the focus and design of interventions to alter prostate cancer screening behavior and their implications for the clinical management of men with urologic symptoms.

Adult↗

PubMed2026

The transposable element-PARP axis underpins synthetic lethality and immunogenic vulnerability in blood cancer.

Transposable elements (TEs) are emerging regulators of hematopoiesis and leukemia, creating vulnerabilities exploitable for therapy. Recent evidence shows that TE reactivation induces innate immune signaling, DNA damage responses, and dependence on poly(ADP-ribose) polymerase (PARP)-mediated protection, enabling synthetic lethality with PARP inhibition even in homologous recombination-proficient leukemias with epigenetic gene mutations. In this article, we highlight the biology underpinning this novel TE-PARP axis, its therapeutic implications, and strategies to expand PARP inhibition beyond HR-deficient cancers through rational combinations with immunotherapy and refined patient stratification.

Humans↗

PubMed2026

Enhancer and metabolic rewiring by KMT2C-COMPASS or KMT2D-COMPASS family loss in cancer creates druggable vulnerabilities.

Many epigenetic regulatory factors are targets of the somatic mutations found in patient tumours. Amongst the family of epigenetic regulatory complexes known as Complex of Proteins Associated with Set1 (COMPASS), the enhancer regulators histone-lysine N-methyltransferase 2C (KMT2C)-COMPASS and KMT2D-COMPASS are particularly critical for differentiation and cell fate specification. Their catalytic subunits, including the histone H3 lysine 4 (H3K4) monomethyltransferases KMT2C (also known as MLL3) and KMT2D (also known as MLL4) and the H3K27-specific demethylase lysine-specific demethylase 6A (KDM6A; also known as UTX), are encoded by some of the most frequently mutated genes across human cancers, particularly epithelial cancers. The multifaceted roles of KMT2C-COMPASS and KMT2D-COMPASS, the variety of KMT2C, KMT2D and KDM6A mutations found across all cancer types, and the tissue-specific impacts of compromised enhancer regulatory function have posed challenges for direct therapeutic targeting. However, KMT2C-COMPASS and KMT2D-COMPASS mutations also create tumour-specific and potentially targetable vulnerabilities. In this Review, we discuss the functional roles of KMT2C-COMPASS and KMT2D-COMPASS and the impact of their mutations on cancer progression. We outline potential therapeutic strategies to exploit vulnerabilities in cancer cells with altered KMT2C-COMPASS or KMT2D-COMPASS activity, including aberrant epigenetic regulatory complex activity, metabolic rewiring, defects in cell-cycle control and DNA repair, and increased immunogenicity.

Humans↗

PubMed2026

Polyamine Metabolism as a Metabolic Vulnerability in Prostate Cancer Treated with Supraphysiological Androgens.

Prostate cancer progression is predominantly driven by androgen receptor (AR) signaling, and despite initial benefits of androgen deprivation therapy (ADT), most patients eventually develop lethal castration-resistant disease. Cyclic administration of supraphysiologic androgen (SPA) with ADT paradoxically suppresses tumor growth; however, responses are heterogeneous, and the mechanisms underlying the antitumor effects of SPA remain incompletely understood. In this issue of Cancer Research, Kumar and colleagues demonstrate that SPA induces a distinct metabolic response, characterized by AR-dependent induction of polyamine biosynthesis via ODC1 and AMD1. This metabolic rewiring elevates polyamine synthesis while concurrently depleting the methyl donor S-adenosylmethionine (SAM). Although increased polyamine metabolism by SPA may promote adaptive resistance, genetic or pharmacologic inhibition of ODC1 using difluoromethylornithine (DFMO) enhances SPA-induced growth suppression by disrupting protective polyamine pools and further exacerbating SAM depletion, revealing a metabolic vulnerability in SPA-treated prostate cancer cells. Supporting these findings, a clinical trial combining DFMO with bipolar androgen therapy (BAT) demonstrated reduced circulating polyamines in patients, confirming polyamine pathway suppression in patients with different genomic features. Together, this study uncovers a mechanistic link among androgen signaling, polyamine metabolism, and therapeutic response, providing a rationale for targeting metabolic dependencies to improve SPA efficacy. See related article by Kumar et al., p. 1148.

Male↗

PubMed2025

A double-negative prostate cancer subtype is vulnerable to SWI/SNF-targeting degrader molecules.

Proteolysis targeting chimera (PROTAC) therapies degrading SWI/SNF ATPases offer a novel approach to interfere with androgen receptor (AR) signaling in AR-dependent castration-resistant prostate cancer (CRPC-AR). To explore the utility of SWI/SNF therapy beyond AR-sensitive CRPC, we investigated SWI/SNF-targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment of cell lines and organoid models reduced the viability of not only CRPC-AR but also WNT-signaling dependent AR-negative CRPC (CRPC-WNT). The CRPC-WNT subgroup represents 11% of around 400,000 cases of CRPC worldwide who die yearly of CRPC. We discovered that SWI/SNF ATPase SMARCA4 depletion interfered with the master transcriptional regulator TCF7L2 (TCF4) in CRPC-WNT. Functionally, TCF7L2 maintains proliferation via the MAPK signaling axis in this subtype of CRPC. These data suggest a mechanistic rationale for interventions that perturb the DNA binding of the pro-proliferative TCF7L2 transcription factor (TF) and/or direct MAPK signaling inhibition in the CRPC-WNT subclass of advanced prostate cancer.

Journal Article↗

PubMed2026

KRAS Expression Complements Genomic Profiling in Identifying Therapeutic Vulnerability in Gastric Cancer.

BACKGROUND: Gastric cancer (GC) remains a major therapeutic challenge. Although alterations in the RAS pathway occur in over 50% of tumors, only a limited proportion are clinically actionable. We investigated whether KRAS expression complements genomic profiling for patient stratification and therapeutic vulnerability in GC. METHODS: Comprehensive genomic profiling was performed in 19 Taiwanese GC patients and compared with TCGA-STAD data (n = 434). KRAS mRNA expression and overall survival were evaluated by meta-analysis of 13 independent cohorts (n = 2,521). Protein-level validation was performed by immunohistochemistry in an independent cohort (n = 121). Functional KRAS dependency and response to combined MEK/SHP2 inhibition were assessed in eight GC cell lines. RESULTS: KRAS amplification was entirely contained within the KRAS-high population, whereas most KRAS-high tumors lacked detectable amplification. High KRAS expression was associated with poorer overall survival (HR 1.23, p = 0.001) and remained an independent prognostic factor after multivariable adjustment (adjusted HR 1.24, p = 0.003). Protein-level analysis showed a concordant trend. KRAS expression correlated strongly with functional dependency (R2 = 0.88, p = 0.005), was enriched in MSI and CIN subtypes, and identified cell lines with enhanced sensitivity to combined MEK/SHP2 inhibition. CONCLUSIONS: KRAS expression complements genomic profiling by identifying biologically relevant KRAS-dependent GCs beyond mutation or amplification alone. Integrating expression-based stratification with genomic profiling may improve patient selection for RAS pathway-directed combination therapies.

Biomarker↗

PubMedDate not supplied

Brief report: health beliefs among survivors of childhood cancer.

OBJECTIVE: To describe interest in cancer screening and tobacco-control procedures (nicotine-addiction susceptibility testing) among survivors of childhood cancer and to identify psychosocial modifying and readiness factors associated with survivors' interest, based on the children's health belief model. METHODS: Twenty-eight survivor-mother dyads were interviewed as part of a preliminary study (mean age of survivors = 15.4 years at time of interview, 10.1 years at time of diagnosis, and 12.0 years at end of treatment); interviews consisted of well-validated self-report items and measures of health beliefs. RESULTS: In sum, 57% and 61% of survivors were interested in screening and susceptibility testing, respectively. Survivors who rated themselves as more competent, more concerned about cancer, and more vulnerable to cancer were more interested in participating in screening. Regarding interest in nicotine-addiction susceptibility testing, survivors were more interested when they perceived greater vulnerability to the harm of smoking and when they had mothers who perceived themselves to be in better health. CONCLUSIONS: Preliminary data suggest that psychosocial modifying and readiness factors are associated with survivors' interest in cancer screening and tobacco-control procedures and that additional research in this area is warranted.

Adolescent↗

PubMed2005

Promoter polymorphism in the matrix metalloproteinase-1 and risk of cervical cancer in Korean women.

The aim of this investigation was to analyze the association between a single nucleotide polymorphism (SNP) in the matrix metalloproteinase (MMP)-1 promoter gene -1607 bp region and cervical cancer risk in Korean women. The blood samples of 232 cervical cancer patients and 332 non-cancer control subjects who managed at Seoul National University Hospital from 1999 to 2002 were collected. Polymorphism in MMP-1 promoter -1607 region was determined using TaqMan method. Allele frequency and genotype distribution in the cervical cancer group were compared with those of the control group to determine whether this polymorphism elevates the susceptibility of Korean women to cervical cancer. The relationship between this SNP and cancer invasiveness was also evaluated by collating clinicopathologic data of those in the cancer group, such as FIGO stage, lymph node status, histologic type and parametrial invasion. In the cervical cancer group, the allele frequency of 2G was 66.1%, in the control group 68.2%, showing no significant difference (P=0.41). Similarly the genotypes with insertion (2G/2G) or deletion (1G/1G) polymorphism showed no increased risk for cervical cancer susceptibility compared with 1G/2G genotype. A subgroup analysis of the clinicopathologic parameters in cancer group also showed no significant difference suggesting the lack of an association between SNP of the MMP-1 promoter -1607 bp region and cervical cancer invasiveness. In conclusion, this study shows that Korean with specific polymorphism in MMP-1 are neither more susceptible to develop cervical cancer nor more vulnerable for cancer progression.

Female↗

PubMed2000

Telomerase inhibitors: targeting the vulnerable end of cancer?

In the past decade, a great deal has been learnt about the maintenance of telomeres in mammalian cells by the specialized reverse transcriptase, telomerase, and its associated proteins. The catalytic component of telomerase, hTERT, appears to be selectively activated in the vast majority of tumors relative to most somatic cells suggesting that its inhibition may result in antitumor effects. Although beset with some unusual issues as a drug target, recent 'target validation' studies using hTERT dominant-negative and antisense approaches strongly support the view that potent and selective telomerase inhibitors will induce inhibitory effects on tumors, especially in those possessing relatively short telomeres. Inhibitory strategies have focused on three main areas: antisense molecules (oligonucleotides, RNA molecules, ribozymes and peptide nucleic acids) directed against the hTR RNA component of telomerase, small molecule reverse transcriptase inhibitors (e.g. azidothymidine), and, probably most advanced, small molecules capable of interacting with and stabilizing four-stranded (G-quadruplex) structures formed by telomeres. G-quadruplex interactive agents that inhibit telomerase at sub-micromolar concentrations in cell-free assays have been described. Lead optimization and preclinical whole-cell and animal antitumor and pharmacology studies are now progressing which should result in the first generation of telomerase inhibitors being evaluated in the clinic within the next few years.

Animals↗

PubMed2001

Anxiety and compliance among women at high risk for breast cancer.

The aim of this study was to investigate the association between symptoms of depression and general anxiety, patient's feelings of vulnerability to cancer, the anxiety experienced specifically in relation to various cancer-screeningprocedures, and compliance with these procedures among women atfamilial risk for breast cancer The data were obtained from 430 patients from the High Risk Clinic at the UCLA Revlon Breast Center who completed the State-Trait Anxiety Inventory and answered questions about their perceived vulnerability to breast cancer; the anxiety they experienced regarding undergoing pap smear tests, mammograms, and breast self-examinations (BSEs); and their compliance with these cancer-screening procedures. Correlations were used to estimate the association between feelings of anxiety and compliance. We found that women attending programs targeting those at familial risk for breast cancer suffer from significant symptoms of general anxiety. General anxiety was found to be related to anxiety regarding specific screening practices but not to women's perceived vulnerability to cancer In general, neither general nor screening-specific anxiety were found to be related to patients 'compliance with screening practices; however, significant associations were found between patient's feelings of anxiety regarding BSEs and their actual performing them. BSE appears to be the only procedure for which compliance is negatively associated with procedure-specific anxiety. We offer possible explanations for this relation and discuss the possible psychological impact that recommendations regarding BSEs may have on highly anxious at-risk women.

Adolescent↗

PubMed1993

Life events, chronic difficulties and vulnerability factors preceding breast cancer.

This study deals with the association between life events, family history of mammary carcinoma and breast cancer. It was guided by a model consisting of events, family disposition and age at the side of the independent variables. In addition to these factors 'lack of social support' was introduced. The latter is conceptualized as a vulnerability factor capable of aggravating the impact of events without having an independent effect. There was no hypothesis on chronic difficulties, so this is exploratory. This research was conducted as a so-called 'limited prospective' design. Women with a suspicious breast lump were interviewed before surgery. After having confirmed the outcome of the surgery the sample was divided into a group with cancer and cases with a benign diagnosis. Women with gall stones were introduced as another control group. The interviews were performed along a semi-structured schedule, tape recorded and analyzed by using Brown and Harris' Life Events and Difficulties Scale. The analyses were made with 33 women with cancer, 59 with a benign tumor and 20 with gall stones. In the 'malignant' group the severest events was four times as high as in controls. All other degrees of threat were equally distributed over the groups. Chronic difficulties of the highest degree of severity also occur more often in the cancer group. They are not independent from events so that analyzing them separately is not useful. The rate of family history of breast cancer does not differ between the tumor groups, but is much lower in the gall stone patients. In the cancer group there is an association between this possibly hereditary factor and severe events, in the 'benign' group both are uncorrelated. The life event effect is explained in context of a higher illness susceptibility due to a hereditary disposition. For events occurring without it an explanation remains unclear.

Adult↗

PubMed2003

Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor.

Current antiestrogen therapy for breast cancer is limited by the mixed estrogenic and antiestrogenic activity of selective estrogen receptor modulators. Here we show that the function of zinc fingers in the estrogen receptor DNA-binding domain (DBD) is susceptible to chemical inhibition by electrophilic disulfide benzamide and benzisothiazolone derivatives, which selectively block binding of the estrogen receptor to its responsive element and subsequent transcription. These compounds also significantly inhibit estrogen-stimulated cell proliferation, markedly reduce tumor mass in nude mice bearing human MCF-7 breast cancer xenografts, and interfere with cell-cycle and apoptosis regulatory gene expression. Functional assays and computational analysis support a molecular mechanism whereby electrophilic agents preferentially disrupt the vulnerable C-terminal zinc finger, thus suppressing estrogen receptor-mediated breast carcinoma progression. Our results provide the proof of principle for a new strategy to inhibit breast cancer at the level of DNA binding, rather than the classical antagonism of estrogen binding.

Antineoplastic Agents, Hormonal↗

PubMed1999

Decision making about prophylactic oophorectomy among at-risk women: psychological influences and implications.

OBJECTIVE: Women with a family history of ovarian cancer are confronted with difficult decisions regarding the management of their risk status. Currently, the main preventive option available is prophylactic oophorectomy. The objective of the present paper is to review research and theory on psychological factors that influence decision making about preventive surgery and discuss the implications for patient management. METHODS: Guided by a cognitive-social framework, the literature on decision making about preventive surgery is reviewed and integrated. RESULTS: The available studies show that women are more likely to opt for surgery if they feel more vulnerable to cancer, believe that surgery will prevent cancer, and are worried about developing cancer. Further, the response to ovarian risk is influenced by the individual's characteristic psychological style: monitors (who typically scan for and amplify threatening cues) tend to feel more vulnerable to cancer and more distressed about their cancer risk than blunters (who typically distract from threatening cues) do. CONCLUSION: On the basis of prior research, monitors may be more likely to choose surgical intervention to reduce their distress, without fully anticipating the psychological and medical consequences of that decision. In order to facilitate informed decision making, counseling protocols should be designed to enable the patient to understand and take account of the psychological consequences of the available medical options. Future studies are needed to systematically extend and explore the proposed theory-based relationships.

Affect↗

PubMed1996

Do calcium channel blockers increase the risk of cancer?

Calcium channel blockers can block calcium signals that trigger cell differentiation and apoptosis, which are important mechanisms of cancer growth regulation. To ascertain whether calcium channel blocker use was associated with an increased risk of cancer, 750 hypertensive persons age > or = 71 years, with no history of cancer at baseline, were followed from 1988 through 1992. The patients were using either beta-blockers, angiotensin converting enzyme inhibitors or calcium channel blockers (verapamil, nifedipine, and diltiazem; mainly of the short-acting variety). Compared to beta-blockers (n = 424, 28 events), after adjusting for age, gender, race, smoking, body mass index, and number of hospital admissions not related with cancer, the relative risks of cancer (95% confidence interval) for angiotensin converting enzyme inhibitors (n = 124, 6 events) and calcium channel blockers (n = 202, 27 events) were 0.73 (0.30 to 1.78) and 2.02 (1.16 to 3.54), respectively. These findings indicate that calcium channel blocker therapy might increase the risk of cancer. New data are needed in patients using modern calcium channel blocker agents with more gradual absorption. This report should encourage further study of cancer outcomes in elderly patients who are vulnerable to cancer and who are receiving calcium channel blockers.

Adrenergic beta-Antagonists↗

PubMed2002

Hypermutable bases in the p53 cancer gene are at vulnerable positions in DNA secondary structures.

A DNA folding analysis indicates that the most hypermutable bases in exons 5, 7, and 8 of the p53 tumor suppressor gene are located immediately next to stems in stable DNA stem-loop structures. On the basis of the highest negative energy (-DeltaG) value of the structures containing each mutable bases and on the extent to which each base is unpaired during transcription, their relative mutabilities are calculated using a new computer algorithm. These predicted mutation frequencies correlate well with those observed in 14,000 human cancers (R(2) = 0.76), whereas there is no such correlation (R(2) = 0.0005) for nearby control bases. The correlation of hypermutable base frequencies with -DeltaG values is poor (R(2) = 0.19), indicating that the extent to which a base is unpaired during transcription is a significant contribution to predicting mutation frequencies.

Bacterial Proteins↗

PubMed1979

Cancer and suicide.

Issues of suicidal ideation, life-threatening behavior, and vulnerability in cancer patients are addressed. A review of pertinent literature is presented, including the areas of: suicide as a taboo topic; incidence of suicide in cancer patients; identifying patients' suicide potential; and suicide as coping behavior. Case examples are offered that illustrate psychiatric intervention with and psychodynamics of cancer patients demonstrating suicidal tendencies.

Adaptation, Psychological↗

PubMed1994

Psychosocial factors in the development and progression of breast cancer.

The factors responsible for the genesis of breast cancer remain unclear. Emerging, although controversial, evidence suggests that factors related to life-style, such as dietary fat or alcohol intake, or exposure to various forms of stressors, are associated with mammary tumorigenesis. The possible role of life-style factors in breast cancer is important in light of the fact that mortality to this disease is increasing in most countries and that development of curative therapies for breast cancer has not been forthcoming. Thus, determining the role of life-style factors in the onset and progression of breast cancer, particularly among individuals genetically vulnerable to breast cancer or women with breast cancer in remission, is critical to prevent this disease. We will review the three main hypotheses which have been suggested to link psychosocial factors to the etiology of cancer, emphasizing data obtained through animal models. Interpretation of the existing data suggests that the number of stressful life-events does not predict vulnerability to develop breast cancer or survival from it; a certain level of stress appears to protect from malignancies. The crucial factor affecting tumor growth is the interaction among stress, an individual's personality, and available psychosocial support, and the effect of this interaction on an individual's ability to cope with stress. In addition, other risk factors for breast cancer known to be closely associated with psychosocial factors, namely dietary fat and alcohol consumption, may interact with the effects of psychosocial factors on breast cancer.

Alcohol Drinking↗

PubMed1994

Cancer, emotional responses and cognitive behavioural psychotherapy.

Cancer and its treatment is known to have a substantial psychological morbidity and, while adjuvant psychological therapy (APT) is well established, relatively little work has been done to investigate the effectiveness of psychotherapy, particularly cognitive behaviour therapy (CBT), for patients with cancer. This article focuses initially on emotional responses to the diagnosis of cancer, individual vulnerability and the prevalence of psychological problems in patients with cancer. The use of cognitive behaviour therapy is then described, together with key issues in its application and specific problems. The work concludes by considering differences in applying CBT to patients with cancer compared to patients with other physical illnesses and the notion of 'relapse inoculation'.

Adaptation, Psychological↗