Participatory development of a home-based depression care model with lived experience older Nigerians and their caregivers: A theory of change.

OBJECTIVES: There is a huge treatment gap for late-life depression in sub-Saharan Africa. Building on prior work to scale-up mental healthcare with the aid of the WHO Mental Health Gap Action Programme Intervention Guide electronic version (emhGAP-IG), this study aims to involve older people in the iterative development of innovations to overcome challenges in the detection and clinical management of late-life depression by frontline non-specialist primary healthcare workers (PHCW) in Nigeria. METHODS: There were 43 participants in the study. We conducted formative qualitative research using 15 in-depth key informant interviews with persons who were 60 years or older and had a recent experience of depression. We also conducted two focus group discussions comprising 13 of their caregivers. Through a full day stakeholders workshop comprising 15 participants, we drew on the results of our qualitative explorations to identify the pathway to impact of an intervention package (emhGAP-Age) appropriate for the specific needs of persons with late-life depression in Nigeria. RESULTS: A Theory of Change (ToC) map was produced. It highlights the expected long-term outcomes of emhGAP-Age to include the potential for improvement of the mental health and wellbeing of older people living in Nigeria and the generation of interest among governmental agencies concerned with policy and planning for mental healthcare. Key resources that serve as preconditions were identified to consist of the availability of PHCW who are skilled in the identification and treatment of depression and have interest in and commitment to providing care to older people. Required community resources include support from immediate family, neighbours, and informal groups. Interventions that are appropriate for depression in old age need to incorporate these community resources and address not only the symptoms of the condition but also comorbid physical health problems. CONCLUSIONS: A participatory ToC process led to the identification of the key components of an age-appropriate version of the emhGAP-IG for delivering care to older persons with depression by PHCW in Nigeria.

Understanding the experiences of people with dementia and their family carers participating in healthcare student dementia education: A mixed-methods evaluation from the time for dementia programme.

BACKGROUND: There is increasing awareness of the potential for positive impacts on student learning from involving people with dementia and family carers within undergraduate teaching. However, research on the experience of people with dementia and their family carers is sparse. This study aimed to evaluate the satisfaction and views of families (people with dementia and their family carers) who volunteered in Time for Dementia (TFD); an educational programme where undergraduate healthcare students visit families at home over a 2-year period. METHODS: Families taking part in TFD completed a satisfaction survey after taking part in the programme (n = 803). Frequencies of satisfaction survey items were summarised and multiple linear regression models for factors associated with total satisfaction scores were produced. Open text responses were analysed using thematic framework analysis as to the most favourable aspects of the programme and areas requiring improvement. RESULTS: Overall satisfaction was high for taking part in TFD, with a perception of contribution, and being of value. There was strong evidence that families enjoyed the experience and would recommend participation to others. Higher numbers of student visits were significantly associated with greater satisfaction. Families identified aspects of the programme that benefited them, with social interaction rating highly. Improvements suggested by the families included increased visit structure and organisational improvements. CONCLUSIONS: This study has sought to evaluate at scale the satisfaction of families taking part in a dementia education programme. It is positive that families report high satisfaction in the programme and identify perceived value for themselves as well as students, suggesting reciprocal benefits. This study contributes to the broader understanding of what Experts by Experience value when taking part in educational interventions.

Time for Dementia: Quantitative evaluation of a dementia education programme for healthcare students.

OBJECTIVES: The future healthcare workforce needs the skills, attitudes, and empathy to better meet the needs of those with dementia. Time for Dementia (TFD) is an educational programme in which healthcare students from a range of professional groups visit a person with dementia and their family carer over a two-year period. The aim of this study was to evaluate its impact on student attitudes, knowledge and empathy towards dementia. METHODS: Measures of dementia knowledge, attitudes and empathy were administered to healthcare students at five universities in the south of England before and after (24 months) they completed the TFD programme. Data were also collected at equivalent time points for a control group of students who had not taken part in the programme. Outcomes were modelled using multilevel linear regression models. RESULTS: 2,700 intervention group students, and 562 control group students consented to participate. Students undertaking the TFD programme had higher levels of knowledge and positive attitudes at follow-up compared to equivalent students who did not undertake the programme. Our findings indicate a positive relationship between the number of visits undertaken and increasing dementia knowledge and attitudes. No substantial differences in the development of empathy was observed between groups. CONCLUSION: Our findings suggest that TFD may be effective across professional training programmes and universities. Further research into the mechanisms of action is needed.

Perception of providers on use of the WHO mental health Gap Action Programme-Intervention Guide (mhGAP-IG) electronic version and smartphone-based clinical guidance in Nigerian primary care settings.

BACKGROUND: Taking advantage of the rapidly increasing access to digital technology in low- and middle-income countries, the World Health Organization has launched an electronic version of the mental health Gap Action Programme intervention guide (emhGAP-IG). This is suitable for use on smartphones or tablets by non-specialist primary healthcare providers (PHCWs) to deliver evidence-based intervention for priority mental, neurological and substance use disorders. We assessed the perceptions of PHCWs on the feasibility, acceptability, and benefits of using smartphone-based clinical guidance and the emhGAP-IG in the management of people with mental health conditions in Nigeria.  METHODS: Exploration of the views of PHCWs from 12 rural and urban primary health clinics (PHCs) in South-Western Nigeria were carried out using 34 in-depth key informant qualitative interviews with nurses (n = 10), community health officers (n = 13) and community health extension workers (n = 11). An additional two focus group discussions, each comprising eight participants drawn from across the range of characteristics of PHCWs, were also conducted. Thematic analysis was conducted using a three-staged constant comparison technique to refine and categorise the data. RESULTS: Three overall themes were identified around the use of clinical guidance and mobile applications (apps) in PHCs. Apps were deployed for purposes other than clinical consultation and decision making. Although paper-based guidance was the expected practice, its utilization is not fully embedded in routine care. An app-based decision-making tool was preferred to paper by PHCWs. Future usage of the emhGAP-IG would be facilitated by training and supporting of staff, helpful design features, and obtaining patients' buy-in. CONCLUSION: Our findings suggest that the emhGAP-IG could be a viable way to embed clinical guidance and decision-making tools in the management of people with mental health conditions in Nigerian PHCs.

Developing undergraduate autism education for medical students: a qualitative study.

BACKGROUND: Autistic adults and children experience considerable health inequalities and have high rates of premature mortality, hospital admissions and emergency department visits. This is in part due to a lack of autism awareness in the healthcare and social care workforce. A new educational programme, Time for Autism (TfA), for medical students is being developed to address this challenge. This qualitative study was undertaken to support the development of the new programme in order to (1) understand the medical care experiences of parents of autistic children and (2) assess their views on the acceptability of the new TfA programme and willingness to be involved. METHODS: A convenience sample of 11 parents of autistic children were recruited across the South of England. The ages of the autistic children ranged from 3 to 17 years. Semistructured interviews were completed between October and December 2019. Interview transcripts were analysed using thematic analysis. RESULTS: Three key themes were identified: diagnosis, experiences of doctors and TfA considerations. There was support for and willingness to take part in a dedicated autism education programme for medical students, and constructive feedback to inform and improve its delivery. CONCLUSION: The findings from this study provide insights into the medical care experiences of parents/carers of autistic children. Understanding how parents/carers of autistic children would like medical care to be improved can be used to develop TfA and other autism programmes. Parental/carer support for the development of and involvement in an autism medical education programme enhances the feasibility of the new programme.

Factors associated with change over time in quality of life of people with dementia: longitudinal analyses from the MODEM cohort study.

BACKGROUND: Research to date offers mixed evidence about the relationship between quality of life and severity of cognitive impairment in people with dementia. We aimed to investigate longitudinal changes in patient- and proxy-rated health-related quality of life (HRQL) by severity of dementia and explore factors associated with changes in HRQL over a one-year period. We used data from the MODEM longitudinal cohort study which recruited dyads of persons with clinically diagnosed dementia and their principal carer and interviewed them face-to-face at baseline and again 1 year later. METHODS: Quota sampling was used to generate balanced numbers (target n = 100 for each severity level) of people with mild cognitive impairment (20+ on the standardised Mini-Mental State Examination (sMMSE)), moderate cognitive impairment (score 10 to 19), and severe cognitive impairment (score 0 to 9). Persons with dementia without an identifiable family carer or other informant (e.g., a formal/professional/paid carer) were excluded from the study. Participants answered a series of questions measuring their HRQL: DEMQOL, DEMQOL-proxy, EQ-5D-3 L, EQ-5D-3L proxy. Multiple regression models were built to understand the effects of baseline demographics and dementia symptoms (cognitive impairment, neuropsychiatric symptoms) on change in HRQL over 1 year. RESULTS: Two hundred and forty-three dyads of people with clinically diagnosed dementia and carers completed baseline and follow-up interviews. Most measures of HRQL remaining relatively stable between time-points, but one index of HRQL, EQ-5D proxy, significantly declined. Depending on the HRQL measure, different factors were associated with change in HRQL. The only factor consistently associated with decline in HRQL (when compared to improvement) was having a diagnosis of a non-Alzheimer's dementia. CONCLUSIONS: Deterioration in HRQL is not an inevitable part of the dementia journey. However, people with non-Alzheimer's dementias may be more susceptible to HRQL decline. This may indicate that those with non-Alzheimer's dementia may benefit from specific support focussed on maintaining their quality of life.

What factors have influenced quality of life in people with dementia and their family carers during the COVID-19 pandemic: a qualitative study.

OBJECTIVES: The COVID-19 pandemic has led to significant disruption to health and social care services. For people with dementia and their family carers this is problematic, as a group who rely on timely and responsive services to live well with the condition. This study has sought to understand how COVID-19 has affected the quality of life of people diagnosed with dementia and their family carers. DESIGN: Our mixed-methods study was nested in a larger cohort study of an education programme, Time for Dementia. SETTING: The study took place in the South-East of England. PARTICIPANTS: Existing study participants, family carers were approached about the COVID-19 nested study. A purposeful sample of participants were invited to take part in in-depth qualitative interview. The sample included family carers in a range of different caring situations. MEASUREMENT: Interviews were undertaken remotely by telephone. Interviews sought to understand quality of life before the pandemic, impact of the restrictions on both the person with dementia and family carer, role of services and other agencies as well as supportive factors. Data were analysed using thematic analysis. RESULTS: 16 family carers were interviewed. Seven themes were identified from our analysis: (1) decreased social interaction; (2) reduced support; (3) deteriorating cognitive and physical health for the person with dementia; (4) decreased carer well-being; (5) difficulties understanding COVID-19 restrictions; (6) limited impact for some and (7) trust and relationship with care home. There was little change between themes during the first and second wave of national lockdowns. CONCLUSIONS: Our study provides an understanding the short-term impact of COVID-19 on the quality of life of people with dementia and their family carers. Our findings suggest that recovery between the first and second wave of the restrictions did not automatically take place.

Covid-19 and the quality of life of people with dementia and their carers-The TFD-C19 study.

INTRODUCTION: COVID-19 has placed unprecedented pressure on dementia health and social care systems worldwide. This has resulted in reduced services and support for people with dementia and their family carers. There are gaps in the evidence on the impact of the pandemic on Quality of Life (QoL). We carried out a study on the impact of the pandemic on the QoL of a group of people with dementia and their family carers who were part of a larger existing cohort study. METHODS: We quantitatively measured QoL, on two occasions during the two national lockdowns in 2020 and compared these data with those obtained when they entered the study (before the pandemic). Measures used included: DEMQOL-Proxy, Clinical Dementia Rating Scale and C-DEMQOL. To understand how QoL changed over time, a repeated measures ANOVA was run for each dependent variable with the following variables entered as co-variates: duration in study, baseline dementia severity, gender of the family carer, gender of the person with dementia, family carer relationship, dementia type, living status, age of the person with dementia, and age of the family carer. RESULTS: 248 participants took part in the study. QoL scores did not significantly decline between either time period for the person with dementia or their family carer. There was variation in subgroups; with co-resident status, carer relationship, gender of the person with dementia, age of the person with dementia, and baseline cognitive status influencing QoL outcomes in family carers. DISCUSSION: It is striking that people with dementia and their carers did not report a decline in QoL during the pandemic or in the months following restrictions suggesting the possibility of resilience. Variation in subgroups suggests that specific groups of family carers were more vulnerable to lower QoL; indicating the need for more tailored, nuanced support during this period.

Barriers and facilitators to implementing a longitudinal dementia education programme into undergraduate healthcare curricula: a qualitative study.

BACKGROUND: As the numbers of people with dementia worldwide rises, there is a need for improved knowledge and awareness about the condition across the healthcare workforce. There are concerns that traditional models of healthcare education, which focus on short-term episodes of care, limit student understanding of long-term conditions. We therefore designed and delivered the Time for Dementia programme at five Universities in the UK. Through longitudinal contact with families living with dementia, healthcare students gain increased understanding about the experiences of living with dementia. However, implementing new educational models brings challenges. To enable implementation of similar programmes in other educational institutions, this study aimed to identify the common barriers and facilitators of implementing these types of longitudinal programmes at scale. METHODS: To understand the facilitators and barriers of implementing a longitudinal dementia educational programme, a qualitative study was completed. Between October and December 2018, twelve in-depth semi-structured interviews were completed with university teaching staff (n = 6), programme administrators (n = 4), and Alzheimer's Society staff (n = 2) that had key responsibilities for implementing Time for Dementia. Interview questions explored participants experiences, the facilitators, and the challenges encountered when implementing the programme. Interviews were audio recorded, transcribed verbatim, and analysed using inductive thematic analysis. RESULTS: The analysis identified five key themes: "Leadership characteristics", "Organisational and student buy-in", "Perceived value and motivating factors", "Team coalition and support", and "Time and fit". Implementation of the programme was enhanced by resilient leaders managing the challenges of curricular change. Their belief in the value of the programme, stakeholder buy-in, and supportive team working enabled challenges to be overcome. Workload was reduced and student buy-in increased as time progressed and as more resources became available. A flexible approach to implementation was recommended to ensure the programme fits within the established curriculum. CONCLUSION: Curricular change is a challenging task, yet necessary, if we are to improve care for people with long term conditions such as dementia. This study highlights the common barriers and facilitators experienced when implementing a longitudinal educational programme at scale. The findings presented in this study can be used by other educational institutions to manage curricular change efforts.

A comparative study of the effect of the Time for Dementia programme on medical students.

BACKGROUND: Traditional healthcare education typically focuses on short block clinical placements based on acute care, investigations and technical aspects of diagnosis and treatment. It may therefore fail to build the understanding, compassion and person-centred empathy needed to help those with long-term conditions, like dementia. Time for Dementia was developed to address this. METHOD: Parallel group comparison of two cohorts of UK medical students from universities, one participating in Time for Dementia (intervention group) and one not (control group). In Time for Dementia students visit a person with dementia and their family in pairs for 2 hours three times a year for 2 years, the control group received their normal curriculum. RESULTS: In an adjusted multilevel model (intervention group n = 274, control n = 112), there was strong evidence supporting improvements for Time for Dementia participants in: total Approaches to Dementia Questionnaire score (coefficient: 2.19, p = 0.003) and its person-centredness subscale (1.32, p = 0.006) and weaker evidence in its hopefulness subscale (0.78, p = 0.070). There was also strong evidence of improvement in the Dementia Knowledge Questionnaire (1.63, p < 0.001) and Dementia Attitudes Scale (total score: 6.55, p < 0.001; social comfort subscale: 4.15, p < 0.001; dementia knowledge subscale: 3.38, p = 0.001) scores. No differences were observed on the Alzheimer's Disease Knowledge Scale, the Medical Condition Regard Scale or the Jefferson Scale of Empathy. DISCUSSION: Time for Dementia may help improve the attitudes of medical students towards dementia promoting a person-centred approach and increasing social comfort. Such patient-focused programmes may be a useful complement to traditional medical education.

A qualitative evaluation of the effect of a longitudinal dementia education programme on healthcare student knowledge and attitudes.

BACKGROUND AND OBJECTIVES: There is a need to ensure that the future healthcare workforce has the necessary knowledge and skills to deliver high quality compassionate care to the increasing number of people with dementia. Our programme has been set up to address this challenge. In the programme, undergraduate healthcare students (nursing, medical and paramedic) visit a family (person with dementia and their carer) in pairs over a 2-year period. This qualitative study sought to understand the student experience of the programme. METHODS: Participants were undergraduate healthcare students who were undertaking our programme at two universities. We sampled for variation in the student participants in order to generate a framework for understanding the student experience of the programme. Students were invited to take part in the qualitative study, and written consent was obtained. Interviews and focus group transcripts were analysed using thematic analysis. RESULTS: Thirty-nine (nursing, medical and paramedic) student participants took part in individual in-depth qualitative interviews and 38 took part in five focus groups. Four key themes were identified from the analysis; relational learning, insight and understanding, challenging attitudes and enhanced dementia practice. DISCUSSION: Student experience of our programme was shown to be positive. The relationship between the students and family was most impactful in supporting student learning, and the subsequent improvement in knowledge, attitudes and practice. Our model of undergraduate dementia education has applicability for other long-term conditions.

Disease severity accounts for minimal variance of quality of life in people with dementia and their carers: analyses of cross-sectional data from the MODEM study.

BACKGROUND: Due to the progressive nature of dementia, it is important to understand links between disease severity and health-related outcomes. The aim of this study is to explore the relationship between disease severity and the quality of life (QoL) of people with dementia and their family carers using a number of disease-specific and generic measures. METHODS: In the MODEM cohort study, three-hundred and seven people with clinically diagnosed dementia and their carers were recruited on a quota basis to provide equal numbers of people with mild (standardised Mini-Mental State Examination (sMMSE), n = 110), moderate (sMMSE 10-19, n = 100), and severe (sMMSE 0-9, n = 97) cognitive impairment. A series of multiple regression models were created to understand the associations between dementia severity and the QoL of people with dementia and the QoL of their carers. QoL was measured using self- (DEMQOL, EQ-5D, CASP-19) and proxy-reports (DEMQOL-Proxy, EQ-5D) of disease-specific and generic QoL of the person with dementia. Carer generic QoL was measured by self-report (EQ-5D, SF-12). RESULTS: Disease severity, as measured by the sMMSE, was not significantly associated with the QoL of the person with dementia or the carer (p > 0.05), even after controlling for potential confounding variables for self-reported instruments. Proxy measures (rated by the carer) differed systematically in that there were small, but statistically significant proportions of the variance of QoL was explained by severity of cognitive impairment in multiple adjusted models. We also found little in the way of statistically significant relationships between the QoL of people with dementia and that of their carers except between DEMQOL-Proxy scores and the carer EQ-5D scores and carer SF-12 mental sub-scores. CONCLUSIONS: The data generated supports the somewhat counterintuitive argument that severity of cognitive impairment (and therefore severity of dementia) is not associated with lower QoL for the person with dementia when self-report measures are used. However, in absolute terms, as judged by the variance in the multivariate models, it is clear that the contribution of dementia severity to the QoL of people with dementia is minimal whatever the measurement used, be it self- or proxy-rated, or disease-specific or generic.

Measuring the quality of life of family carers of people with dementia: development and validation of C-DEMQOL.

PURPOSE: We aimed to address gaps identified in the evidence base and instruments available to measure the quality of life (QOL) of family carers of people with dementia, and develop a new brief, reliable, condition-specific instrument. METHODS: We generated measurable domains and indicators of carer QOL from systematic literature reviews and qualitative interviews with 32 family carers and 9 support staff, and two focus groups with 6 carers and 5 staff. Statements with five tailored response options, presenting variation on the QOL continuum, were piloted (n = 25), pre-tested (n = 122) and field-tested (n = 300) in individual interviews with family carers from North London and Sussex. The best 30 questions formed the C-DEMQOL questionnaire, which was evaluated for usability, face and construct validity, reliability and convergent/discriminant validity using a range of validation measures. RESULTS: C-DEMQOL was received positively by the carers. Factor analysis confirmed that C-DEMQOL sum scores are reliable in measuring overall QOL (ω = 0.97) and its five subdomains: 'meeting personal needs' (ω = 0.95); 'carer wellbeing' (ω = 0.91); 'carer-patient relationship' (ω = 0.82); 'confidence in the future' (ω = 0.90) and 'feeling supported' (ω = 0.85). The overall QOL and domain scores show the expected pattern of convergent and discriminant relationships with established measures of carer mental health, activities and dementia severity and symptoms. CONCLUSIONS: The robust psychometric properties support the use of C-DEMQOL in evaluation of overall and domain-specific carer QOL; replications in independent samples and studies of responsiveness would be of value.

Cyclophilin A Function in Mammary Epithelium Impacts Jak2/Stat5 Signaling, Morphogenesis, Differentiation, and Tumorigenesis in the Mammary Gland.

The prolyl isomerase cyclophilin A (CypA) regulates the Jak2/Stat5 pathway, which is necessary for mammary differentiation and the pathogenesis of breast cancer. In this study, we assessed the role of this isomerase during mammary gland development and erbB2-driven tumorigenesis. Genetic deletion of CypA resulted in delayed mammary gland morphogenesis and differentiation with corresponding decrease in Jak2/Stat5 activation; mammary gland cross-transplantation confirmed this defect was epithelial in nature. Analysis of mammary stem and progenitor populations revealed significant disruption of epithelial maturation. Loss of CypA in the erbB2 transgenic mouse model revealed a marked increase in mammary tumor latency that correlated with decreased Stat5 activation, associated gene expression, and reduced epithelial cell proliferation. These results demonstrate an important role for CypA in the regulation of Jak2/Stat5-mediated biology in mammary epithelium, identifying this isomerase as a novel target for therapeutic intervention.Significance: These findings reveal cyclophilin A functions in normal mammary epithelial development and ErbB2-driven mammary tumorigenesis and suggest therapies targeting cyclophilin A may be efficacious for breast cancer treatment.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3877/F1.large.jpg Cancer Res; 78(14); 3877-87. ©2018 AACR.

HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth.

Stat5a is a transcription factor utilized by several cytokine/hormone receptor signaling pathways that promotes transcription of genes associated with proliferation, differentiation, and survival of cancer cells. However, there are currently no clinically approved therapies that directly target Stat5a, despite ample evidence that it contributes to breast cancer pathogenesis. Here, deacetylation of the Stat5a coactivator and chromatin-remodeling protein HMGN2 on lysine residue K2 by HDAC6 promotes Stat5a-mediated transcription and breast cancer growth. HDAC6 inhibition both in vitro and in vivo enhances HMGN2 acetylation with a concomitant reduction in Stat5a-mediated signaling, resulting in an inhibition of breast cancer growth. Furthermore, HMGN2 is highly acetylated at K2 in normal human breast tissue, but is deacetylated in primary breast tumors and lymph node metastases, suggesting that targeting HMGN2 deacetylation is a viable treatment for breast cancer. Together, these results reveal a novel mechanism by which HDAC6 activity promotes the transcription of Stat5a target genes and demonstrate utility of HDAC6 inhibition for breast cancer therapy. IMPLICATIONS: HMGN2 deacetylation enhances Stat5a transcriptional activity, thereby regulating prolactin-induced gene transcription and breast cancer growth. Mol Cancer Res; 14(10); 994-1008. ©2016 AACR.

Immunoassay and Nb2 lymphoma bioassay prolactin levels and mammographic density in premenopausal and postmenopausal women the Nurses' Health Studies.

Higher circulating prolactin levels have been associated with higher percent mammographic density among postmenopausal women in some, but not all studies. However, few studies have examined associations with dense area and non-dense breast area breast or considered associations with prolactin Nb2 lymphoma cell bioassay levels. We conducted a cross-sectional study among 1,124 premenopausal and 890 postmenopausal women who were controls in breast cancer case-control studies nested in the Nurses' Health Study (NHS) and NHSII. Participants provided blood samples in 1989-1990 (NHS) or 1996-1999 (NHSII) and mammograms were obtained from around the time of blood draw. Multivariable linear models were used to assess the associations between prolactin levels (measured by immunoassay or bioassay) with percent density, dense area, and non-dense area. Among 1,124 premenopausal women, percent density, dense area, and non-dense area were not associated with prolactin immunoassay levels in multivariable models (p trends = 0.10, 0.18, and 0.69, respectively). Among 890 postmenopausal women, those with prolactin immunoassay levels in the highest versus lowest quartile had modestly, though significantly, higher percent density (difference = 3.01 percentage points, 95 % CI 0.22, 5.80) as well as lower non-dense area (p trend = 0.02). Among women with both immunoassay and bioassay levels, there were no consistent differences in the associations with percent density between bioassay and immunoassay levels. Postmenopausal women with prolactin immunoassay levels in the highest quartile had significantly higher percent density as well as lower non-dense area compared to those in the lowest quartile. Future studies should examine the underlying biologic mechanisms, particularly for non-dense area.

Bioactive prolactin levels and risk of breast cancer: a nested case-control study.

BACKGROUND: Prolactin is a lactogenic hormone associated with breast cancer risk in prospective studies, which used immunoassays. The immunoassay captures multiple isoforms and may not fully reflect the biologic activity of prolactin relevant to breast carcinogenesis. METHODS: We considered plasma bioactive prolactin levels measured by the Nb2 lymphoma cell bioassay, which is sensitive to the somatolactogenic activity of prolactin and growth hormone, within a nested case-control study of invasive breast cancer in the Nurses' Health Studies (NHS/NHSII). We also considered associations with breast cancer risk factors. RESULTS: We had bioassay measures on 1,329 cases and 1,329 controls. Bioassay levels were inversely associated with parity (4+ vs. 0 children = -18%, P = 0.01), body mass index (30+ vs. <22 kg/m(2) = -16%, P < 0.01), and age at menopause (53+ vs. 48 years = -18%, P = 0.03) and positively with family history of breast cancer (yes vs. no = 14%, P < 0.01). The relative risk (RR) comparing the top versus bottom quartile of bioassay levels was 1.19 [95% confidence intervals (CI), 0.94-1.51; Ptrend = 0.18]. The association was suggestively stronger for postmenopausal (RR = 1.36; 95% CI, 0.93-1.98; Ptrend = 0.12) versus premenopausal women (RR = 0.99; 95% CI, 0.71-1.37; Ptrend = 0.71). There was an association for cases diagnosed <4 years after blood draw (RR = 2.66; 95% CI, 1.45-4.89; Ptrend < 0.01), but not for cases diagnosed later. We did not observe differential associations by estrogen receptor status or other tumor characteristics. CONCLUSIONS: Our results show similar associations for prolactin levels measured by bioassay and by immunoassay with both breast cancer risk factors and risk. IMPACT: Future work examining risk prediction model of breast cancer can use the immunoassay to accurately characterize risk.

Hormonal determinants of nipple aspirate fluid yield among breast cancer cases and screening controls.

BACKGROUND: Nipple aspiration fluid (NAF) use as a biosample is limited by the variable yield across studies. We investigated the endocrine determinants of yield in an ongoing breast cancer case-control study. METHODS: One-hundred and eighteen women yielding ≥2 µL NAF and 120 non-yielders were included; serum hormones were measured; differences in median hormones were assessed using the Wilcoxon rank-sum test. ORs and 95% confidence intervals (95% CI) for yielder status relative to hormone levels were estimated using logistic regression, adjusting for parity and lactation, and, in premenopausal women, menstrual cycle phase (MCP). RESULTS: Prolactin concentrations were higher in yielders than non-yielders (premenopausal: 7.6 and 2.5 ng/mL, P < 0.01; postmenopausal 5.3 and 2.2 ng/mL; P < 0.01). Among premenopausal-yielders, estradiol was lower (64.3 vs. 90.5 pg/mL, MCP-adjusted P = 0.02). In separate menopausal status and parity-adjusted models, significant case-control differences persisted in prolactin: case OR 1.93 (95% CI, 1.35-2.77), control OR 1.64 (95% CI, 1.17-2.29). Premenopausal control yielders had higher progesterone (OR, 1.70; 95% CI, 1.18-2.46) and sex-hormone binding-globulin (OR, 2.09; 95% CI, 1.08-4.05) than non-yielders. Among parous women, further adjustment for lactation suggested a stronger positive association of serum prolactin with yield in cases than controls. CONCLUSION: NAF-yielders show higher prolactin than non-yielders, regardless of menopause and parity; implications of this and other endocrine differences on NAF biomarkers of breast cancer risk deserve further study. IMPACT: NAF yield is associated with a distinct endocrine environment that must be considered in studies of NAF-based breast cancer risk markers.

The prolactin receptor transactivation domain is associated with steroid hormone receptor expression and malignant progression of breast cancer.

The polypeptide hormone prolactin (PRL) stimulates breast epithelial cell growth, differentiation, and motility through its cognate receptor, PRLr. PRLr is expressed in most breast cancers; however, its exact role remains elusive. Our laboratory previously described a novel mode of PRLr signaling in which Stat5a-mediated transcription is regulated through ligand-induced phosphorylation of the PRLr transactivation domain (TAD). Herein, we used a PRLr transactivation-deficient mutant (PRLrYDmut) to identify novel TAD-specific target genes. Microarray analysis identified 120 PRL-induced genes up-regulated by wild type but not PRLrYDmut. Compared with control, PRLr expression significantly induced expression of approximately 4700 PRL-induced genes, whereas PRLrYDmut ablated induction of all but 19 of these genes. Ingenuity pathway analysis found that the PRLr TAD most profoundly affected networks involving cancer and proliferation. In support of this, PRLrYDmut expression reduced anchorage-dependent and anchorage-independent growth. In addition, pathway analysis identified a link between the PRLr TAD and the estrogen and progesterone receptors (ERα/PR). Although neither ERα nor PR was identified as a PRL target gene, a TAD mutation significantly impaired ERα/PR expression and estrogen responsiveness. TMA analysis revealed a marked increase in nuclear, but not cytoplasmic, PRLr TAD phosphorylation as a function of neoplastic progression. We propose that PRLr TAD phosphorylation contributes to breast cancer pathogenesis, in part through regulation of ERα and PR, and has potential utility as a biomarker in this disease.

HMGN2 inducibly binds a novel transactivation domain in nuclear PRLr to coordinate Stat5a-mediated transcription.

The direct actions of transmembrane receptors within the nucleus remain enigmatic. In this report, we demonstrate that the prolactin receptor (PRLr) localizes to the nucleus where it functions as a coactivator through its interactions with the latent transcription factor signal transducer and activator of transcription 5a (Stat5a) and the high-mobility group N2 protein (HMGN2). We identify a novel transactivation domain within the PRLr that is activated by ligand-induced phosphorylation, an event coupled to HMGN2 binding. The association of the PRLr with HMGN2 enables Stat5a-responsive promoter binding, thus facilitating transcriptional activation and promoting anchorage-independent growth. We propose that HMGN2 serves as a critical regulatory factor in Stat5a-driven gene expression by facilitating the assembly of PRLr/Stat5a onto chromatin and that these events may serve to promote biological events that contribute to a tumorigenic phenotype. Our data imply that phosphorylation may be the molecular switch that activates a cell surface receptor transactivation domain, enabling it to tether chromatin-modifying factors, such as HMGN2, to target promoter regions in a sequence-specific manner.