Influence of patient and tumor characteristics on early therapy persistence with letrozole in postmenopausal women with early breast cancer: results of the prospective Evaluate-TM study with 3941 patients.

Background: Patients' compliance and persistence with endocrine treatment has a significant effect on the prognosis in early breast cancer (EBC). The purpose of this analysis was to identify possible reasons for non-persistence, defined as premature cessation of therapy, on the basis of patient and tumor characteristics in individuals receiving adjuvant treatment with letrozole. Patients and methods: The EvAluate-TM study is a prospective, multicenter, noninterventional study in which treatment with the aromatase inhibitor letrozole was evaluated in postmenopausal women with hormone receptor-positive EBC in the early therapy phase. Treatment persistence was evaluated at two pre-specified study visits after 6 and 12 months. As a measure of early therapy persistence the time from the start to the end of treatment (TTEOT) was analyzed. Cox regression analyses were carried out to identify patient characteristics and tumor characteristics predicting TTEOT. Results: Out of the total population of 3941 patients with EBC, 540 (13.7%) events involving treatment cessation unrelated to disease progression were observed. This was due to drug-related toxicity in the majority of cases (73.5%). Persistence rates were 92.2%, 86.9%, and 86.3% after 6, 12, and 15 months, respectively. The main factors influencing premature treatment discontinuation were older age [hazard ratio (HR) 1.02/year], comorbidities (HR 1.06 per comorbidity), low body mass index, and lower tumor grade (HR 0.85 per grade unit). Conclusion: These results support the view that older, multimorbid patients with low tumor grade and low body mass index are at the greatest risk for treatment discontinuation and might benefit from compliance and support programs.

Systematic comparative validation of self-report measures of sedentary time against an objective measure of postural sitting (activPAL).

BACKGROUND: Sedentary behaviour is a public health concern that requires surveillance and epidemiological research. For such large scale studies, self-report tools are a pragmatic measurement solution. A large number of self-report tools are currently in use, but few have been validated against an objective measure of sedentary time and there is no comparative information between tools to guide choice or to enable comparison between studies. The aim of this study was to provide a systematic comparison, generalisable to all tools, of the validity of self-report measures of sedentary time against a gold standard sedentary time objective monitor. METHODS: Cross sectional data from three cohorts (N = 700) were used in this validation study. Eighteen self-report measures of sedentary time, based on the TAxonomy of Self-report SB Tools (TASST) framework, were compared against an objective measure of postural sitting (activPAL) to provide information, generalizable to all existing tools, on agreement and precision using Bland-Altman statistics, on criterion validity using Pearson correlation, and on data loss. RESULTS: All self-report measures showed poor accuracy compared with the objective measure of sedentary time, with very wide limits of agreement and poor precision (random error > 2.5 h). Most tools under-reported total sedentary time and demonstrated low correlations with objective data. The type of assessment used by the tool, whether direct, proxy, or a composite measure, influenced the measurement characteristics. Proxy measures (TV time) and single item direct measures using a visual analogue scale to assess the proportion of the day spent sitting, showed the best combination of precision and data loss. The recall period (e.g. previous week) had little influence on measurement characteristics. CONCLUSION: Self-report measures of sedentary time result in large bias, poor precision and low correlation with an objective measure of sedentary time. Choice of tool depends on the research context, design and question. Choice can be guided by this systematic comparative validation and, in the case of population surveillance, it recommends to use a visual analog scale and a 7 day recall period. Comparison between studies and improving population estimates of average sedentary time, is possible with the comparative correction factors provided.

Comparison of single- and dual-monitor approaches to differentiate sitting from lying in free-living conditions.

High levels of sedentary time have been detrimentally linked to health outcomes. Differentiating sitting from lying may help to further understand the mechanisms associated with these health impacts. This study compares the inter-method agreement between the "single-monitor" method (thigh-worn activPAL3TM ) and a more robustly validated "dual-monitor" method (trunk and thigh-worn activPAL3TM ) in their classifications of sitting and lying under free-living conditions. Thirty-five participants (20-50 years) wore two activity monitors (thigh and trunk) for 24 hours. Total time spent lying and sitting was calculated for both methods, and agreement was determined using ICC and Bland-Altman methods. As there was no gold standard, further data were collected from five participants during structured activities that were designed to challenge classification, to better understand any disagreement between the methods. ICCs were 0.81 for sitting time and 0.64 for lying time. The single-monitor method detected less lying time than the dual-monitor method, with a mean difference of -25 minutes (95% agreement limits: -172 to 221 minutes), including three cases with extreme disagreement (mostly in daytime lying classification). The additional data collection suggested a major source of disagreement was failure of the single-monitor method to identify lying that involved no rotation around the longitudinal axis. In conclusion, there was some agreement between the single- and dual-monitor estimates of lying time under free-living conditions, but measures were not interchangeable. The main disagreement was in how the methods classified daytime lying and lying tasks involving no lateral movement. Both methods yield promise for measuring time in bed.

The Effect of Structured Patient Education on Physical Activity in Patients with Peripheral Arterial Disease and Intermittent Claudication: A Systematic Review.

OBJECTIVES: The aim was review the components and effects of patient education interventions to improve physical activity (PA) in patients with peripheral arterial disease (PAD) and intermittent claudication (IC), and patients' experiences of these interventions. DATA SOURCES: CINAHL, Cochrane Library, Ovid, ProQuest, AMED, MEDLINE, PsycINFO, Web of Science Core Collection, and PEDRO, and Trial registers and directory of Open Access repository websites and Web of science conference proceedings were searched. Hand searching of reference lists of identified studies was also performed to identify studies that reported the effect of patient education interventions on daily PA and/or walking capacity in individuals with PAD and IC, or studies investigating patients' experiences of such interventions. METHODS: A systematic search was conducted in June 2016 (updated in March 2017). Primary outcomes were daily step count and self reported PA; the secondary outcome was absolute claudication distance. There was substantial heterogeneity in terms of modalities of patient education in the included studies; hence a narrative synthesis was implemented. RESULTS: Six studies (1087 participants) were included in the review. Findings from a small number of high quality trials demonstrated potential for PA improvement with structured education interventions. Nevertheless, evidence is currently inconclusive regarding the effect on daily PA and walking capacity of patients with IC. Patients reported that they valued the interventions studied, finding them acceptable and important in improving their PA, motivating and empowering them to self manage their condition. CONCLUSIONS: The evidence from the review is limited and inconclusive regarding the effectiveness of structured education for increasing PA in patients with PAD and IC. More rigorous trials are needed before recommendations can be made. Future interventions should consider the key criteria for a structured patient education programme, and also report patients' experiences and perceptions.

Feasibility of a laboratory-based protocol for measuring energy expenditure and accelerometer calibration in adults with intellectual disabilities.

Adults with intellectual disabilities experience numerous health inequalities. Targeting unhealthy lifestyle behaviours, such as high levels of sedentary behaviour and overweight/obesity, is a priority area for improving the health and adults with intellectual disabilities and reducing inequalities. Energy expenditure is a fundamental component of numerous health behaviours and an essential component of various free-living behaviour measurements, e.g. accelerometry. However, little is known about energy expenditure in adults with intellectual disabilities and no population-specific accelerometer data interpretation methods have been calibrated. The limited research in this area suggests that adults with intellectual disabilities have a higher energy expenditure, which requires further exploration, and could have significant impacts of device calibration. However, due to the complex methods required for measuring energy expenditure, it is essential to first evaluate feasibility and develop an effective protocol. This study aims to test the feasibility of a laboratory-based protocol to enable the measurement of energy expenditure and accelerometer calibration in adults with intellectual disabilities.We aimed to recruit ten adults (≥ 18 years) with intellectual disabilities. The protocol involved a total of nine sedentary, stationary, and physical activities, e.g. sitting, lying down, standing, and treadmill walking. Each activity was for 5 min, with one 10 min lying down activity to measure resting energy expenditure. Breath by breath respiratory gas exchange and accelerometry (ActiGraph and ActivPAL) were measured during each activity. Feasibility was assessed descriptively using recruitment and outcome measurement completion rates, and participant/stakeholder feedback.Ten adults (N = 7 female) with intellectual disabilities participated in this study. The recruitment rate was 50% and 90% completed the protocol and all outcome measures. Therefore, the recruitment strategy and protocol are feasible.This study addresses a significant gap in our knowledge relating to exercise laboratory-based research for adults with intellectual disabilities The findings from this study provide essential data that can be used to inform the development of future protocols to measure energy expenditure and for accelerometer calibration in adults with intellectual disabilities.

Development and validation of a physical activity monitor for use on a wheelchair.

STUDY DESIGN: Keeping physically active is important for people who mobilize using a wheelchair. However, current tools to measure physical activity in the wheelchair are either not validated or limited in their application. The purpose of this study was to develop and validate a monitoring system to measure wheelchair movement. METHODS: The system developed consisted of a tri-axial accelerometer placed on the wheel of a wheelchair and an analysis algorithm to interpret the acceleration signals. The two accelerometer outputs in the plane of the wheel were used to calculate the angle of the wheel. From this, outcome measures of wheel revolutions, absolute angle and duration of movement were derived and the direction of movement (forwards or backwards) could be distinguished. Concurrent validity was assessed in comparison with video analysis in 14 people with spinal cord injury using their wheelchair on an indoor track and outdoor wheelchair skills course. Validity was assessed using intraclass correlation coefficients (ICC(2,1)) and Bland-Altman plots. RESULTS: The monitoring system demonstrated excellent validity for wheel revolutions, absolute angle and duration of movement (ICC(2,1)>0.999, 0.999, 0.981, respectively) in both manual and powered wheelchairs, when the wheelchair was propelled forwards and backwards, and for movements of various durations. CONCLUSION: This study has found this monitoring system to be an accurate and objective tool for measuring detailed information on wheelchair movement and maneuvering regardless of the propulsion technique, direction and speed.

Cox regression survival analysis with compositional covariates: Application to modelling mortality risk from 24-h physical activity patterns.

Survival analysis is commonly conducted in medical and public health research to assess the association of an exposure or intervention with a hard end outcome such as mortality. The Cox (proportional hazards) regression model is probably the most popular statistical tool used in this context. However, when the exposure includes compositional covariables (that is, variables representing a relative makeup such as a nutritional or physical activity behaviour composition), some basic assumptions of the Cox regression model and associated significance tests are violated. Compositional variables involve an intrinsic interplay between one another which precludes results and conclusions based on considering them in isolation as is ordinarily done. In this work, we introduce a formulation of the Cox regression model in terms of log-ratio coordinates which suitably deals with the constraints of compositional covariates, facilitates the use of common statistical inference methods, and allows for scientifically meaningful interpretations. We illustrate its practical application to a public health problem: the estimation of the mortality hazard associated with the composition of daily activity behaviour (physical activity, sitting time and sleep) using data from the U.S. National Health and Nutrition Examination Survey (NHANES).

Differences in physical activity time-use composition associated with cardiometabolic risks.

This study investigates the association between the overall physical activity composition of the day (sedentary behavior (SB), light intensity physical activity (LIPA) and moderate-to-vigorous physical activity (MVPA)) and cardiometabolic health, and examines whether improved health can be associated with replacing SB with LIPA. A cross-sectional analysis of the Health Survey for England 2008 on N = 1411 adults was undertaken using a compositional analysis approach to examine the relationship between cardiometabolic risk biomarkers and physical activity accounting for co-dependency between relative amounts of time spent in different behavior. Daily time spent in SB, LIPA and MVPA was determined from waist-mounted accelerometry data (Actigraph GT1M) and modelled against BMI, waist circumference, waist-to-hip ratio, blood pressure, total and HDL cholesterol, HbA1c, and VO2 maximum. The composition of time spent in SB, LIPA and MVPA was statistically significantly associated with BMI, waist circumference, waist-to-hips ratio, HDL cholesterol and VO2 maximum (p < 0.001), but not HbA1c, systolic and diastolic blood pressure, or total cholesterol. Increase of relative time spent in MVPA was beneficially associated with obesity markers, HDL cholesterol, and VO2 maximum, and SB with poorer outcomes. The association of changes in LIPA depended on whether it displaced MVPA or SB. Increasing the proportion of MVPA alone may have the strongest potential association with adiposity outcomes and HDL cholesterol but similar outcomes could also be associated with a lower quantity of MVPA provided a greater quantity of SB is replaced overall with LIPA (around 10.5 min of LIPA is equivalent to 1 min of MVPA).

Characteristics of a protocol to collect objective physical activity/sedentary behaviour data in a large study: Seniors USP (understanding sedentary patterns).

The Seniors USP study measured sedentary behaviour (activPAL3, 9 day wear) in older adults. The measurement protocol had three key characteristics: enabling 24-hour wear (monitor location, waterproofing); minimising data loss (reducing monitor failure, staff training, communication); and quality assurance (removal by researcher, confidence about wear). Two monitors were not returned; 91% (n=700) of returned monitors had 7 valid days of data. Sources of data loss included monitor failure (n=11), exclusion after quality assurance (n=5), early removal for skin irritation (n=8) or procedural errors (n=10). Objective measurement of physical activity and sedentary behaviour in large studies requires decisional trade-offs between data quantity (collecting representative data) and utility (derived outcomes that reflect actual behaviour).

Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study.

BACKGROUND: Endocrine treatment (ET) with an aromatase inhibitor (AI) is the treatment of choice in post-menopausal patients with hormone receptor-positive early breast cancer (EBC). However, adverse events (AEs) often lead to treatment discontinuation. This analysis aimed to identify side-effects that lead to patients failing to persist with letrozole treatment. PATIENTS AND METHODS: Post-menopausal hormone receptor-positive EBC patients starting ET with letrozole were enroled in EvAluate-TM, a non-interventional study. Information regarding treatment compliance and persistence was gathered in months 6 and 12. Persistence was defined as the time from 30 d after the start to the end of treatment. The influence on persistence of musculoskeletal syndrome, menopausal disorder, sleep disorder and other AEs within the first 30 d was analysed using Cox regression analyses. RESULTS: Among 3887 patients analysed, the persistence rate after 12 months was >85%. In all, 568 patients (14.6%) discontinued the treatment, 358 of whom (63.0%) did so only because of side-effects. The main AEs influencing persistence were musculoskeletal symptoms (hazard ratio [HR] 2.55; 95% confidence interval [CI], 1.90-3.42), sleep disorders (HR 1.95; 95% CI, 1.41-2.70) and other AEs (HR 2.03; 95% CI, 1.51-2.73). Menopausal disorder was not associated with non-persistence (HR 1.17; 95% CI, 0.74-1.84). CONCLUSIONS: These results suggest that side-effects of AIs such as musculoskeletal syndrome and sleep disorder lead to ET discontinuation within the first treatment year in significant numbers of EBC patients. Compliance programmes adapted for subgroups that are at risk for early non-persistence might help to ensure the recommended therapy duration. CLINICAL TRIALS NUMBER: CFEM345DDE19.

Continuous monitoring of upper-limb activity in a free-living environment: a validation study.

Monitoring upper-limb activity in a free-living environment is important for the evaluation of rehabilitation. This study is a validation of the Strathclyde Upper-Limb Activity Monitor (SULAM) which records the vertical movement and position of each wrist, and assesses bimanual movement. Agreement between the SULAM and two independent video observers was assessed using interclass correlation coefficients (ICC) and the Bland and Altman method. Concurrent validity was very good for movement of each upper-limb (ICC > 0.9), and good for the vertical position of the wrist (ICC > 0.8 for wrist positions below the shoulder, ICC > 0.6 otherwise). The ICC was good (>0.8) for bimanual movement, however the SULAM systematically underreported this by approximately 15%. The SULAM could be a useful tool to assess upper-limb activity of clinical populations in their usual environment.

TAxonomy of Self-reported Sedentary behaviour Tools (TASST) framework for development, comparison and evaluation of self-report tools: content analysis and systematic review.

OBJECTIVE: Sedentary behaviour (SB) has distinct deleterious health outcomes, yet there is no consensus on best practice for measurement. This study aimed to identify the optimal self-report tool for population surveillance of SB, using a systematic framework. DESIGN: A framework, TAxonomy of Self-reported Sedentary behaviour Tools (TASST), consisting of four domains (type of assessment, recall period, temporal unit and assessment period), was developed based on a systematic inventory of existing tools. The inventory was achieved through a systematic review of studies reporting SB and tracing back to the original description. A systematic review of the accuracy and sensitivity to change of these tools was then mapped against TASST domains. DATA SOURCES: Systematic searches were conducted via EBSCO, reference lists and expert opinion. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: The inventory included tools measuring SB in adults that could be self-completed at one sitting, and excluded tools measuring SB in specific populations or contexts. The systematic review included studies reporting on the accuracy against an objective measure of SB and/or sensitivity to change of a tool in the inventory. RESULTS: The systematic review initially identified 32 distinct tools (141 questions), which were used to develop the TASST framework. Twenty-two studies evaluated accuracy and/or sensitivity to change representing only eight taxa. Assessing SB as a sum of behaviours and using a previous day recall were the most promising features of existing tools. Accuracy was poor for all existing tools, with underestimation and overestimation of SB. There was a lack of evidence about sensitivity to change. CONCLUSIONS: Despite the limited evidence, mapping existing SB tools onto the TASST framework has enabled informed recommendations to be made about the most promising features for a surveillance tool, identified aspects on which future research and development of SB surveillance tools should focus. TRIAL REGISTRATION NUMBER: International prospective register of systematic reviews (PROPSPERO)/CRD42014009851.

Gene therapy for carcinoma of the breast.

In view of the limited success of available treatment modalities for breast cancer, alternative and complementary strategies need to be developed. The delineation of the molecular basis of breast cancer provides the possibility of specific intervention by gene therapy through the introduction of genetic material for therapeutic purposes. In this regard, several gene therapy approaches for carcinoma of the breast have been developed. These approaches can be divided into six broad categories: (1) mutation compensation, (2) molecular chemotherapy, (3) proapoptotic gene therapy, (4) antiangiogenic gene therapy, (5) genetic immunopotentiation, and (6) genetic modulation of resistance/sensitivity. Clinical trials for breast cancer have been initiated to evaluate safety, toxicity, and efficacy. Combined modality therapy with gene therapy and chemotherapy or radiation therapy has shown promising results. It is expected that as new therapeutic targets and approaches are identified and advances in vector design are realized, gene therapy will play an increasing role in clinical breast cancer treatment.

Employment of liver tissue slice analysis to assay hepatotoxicity linked to replicative and nonreplicative adenoviral agents.

Whereas virotherapy has emerged as a novel and promising approach for neoplastic diseases, appropriate model systems have hampered preclinical evaluation of candidate conditionally replicative adenovirus agents (CRAds) with respect to liver toxicity. This is due to the inability of human viral agents to cross species. We have recently shown the human liver tissue slice model to be a facile means to validate adenoviral replication. On this basis, we sought to determine whether our ex vivo liver tissue slice model could be used to assess CRAd-mediated liver toxicity. We analyzed and compared the toxicity of a conditionally replicative adenovirus (AdDelta24) to that of a replication incompetent adenovirus (Adnull [E1-]) in mouse and human liver tissue slices. To accomplish this, we examined the hepatic apoptosis expression profile by DNA microarray analyses, and compared these results to extracellular release of aminotransferase enzymes, along with direct evidence of apoptosis by caspase-3 immunhistochemical staining and TUNEL assays. Human and mouse liver tissue slices demonstrated a marked increase in extracellular release of aminotransferase enzymes on infection with AdDelta24 compared to Adnull. AdDelta24-mediated liver toxicity was further demonstrated by apoptosis induction, as detected by caspase-3 immunohistochemical staining, TUNEL assay and microarray analysis. In conclusion, concordance of CRAd-mediated apoptosis in both the human and the mouse liver tissue slice models was demonstrated, despite the limited replication ability of CRAds in mouse liver slices. The results of this study, defining the CRAd-mediated apoptosis gene expression profiles in human and mouse liver, may lay a foundation for preclinical liver toxicity analysis of CRAd agents.

Surface protein expression and messenger RNA-splicing analysis of CD44 in uterine cervical cancer and normal cervical epithelium.

Variant CD44 has recently been shown to serve as a metastasis marker in human breast cancer. Certain variant epitopes on primary tumors predict poor survival probabilities for the patients. In this study, immunohistochemical analysis of 16 uterine cervical carcinomas showed strong expression of several CD44 variant epitopes in all samples. In normal cervical epithelia from 5 patients, expression of these epitopes was restricted to particular cell layers, with expression being strong in basal and spinal cells but absent in superficial cells. Fifteen of 16 cancer samples were stained strongly with an antibody which recognizes one particular CD44 epitope that is encoded by both variant exons v7 and v8. This epitope was not detectable in normal cervical epithelium. CD44-mRNA splicing analysis showed qualitative and quantitative differences between malignant and normal tissues with a much more complex splice pattern and high expression of a large CD44 isoform containing variant exons v3 to v10 (including the v7/v8 transition epitope) in about one-half of the cancer samples. Interestingly, patients with lymph node metastases were in this group only. These differences in CD44 epitope expression and mRNA splicing in cervical carcinoma reveal dynamic changes in CD44 expression during carcinogenesis. Such changes could provide metastatic cells with a selective advantage during the carcinogenic process. Furthermore, the v7/v8 epitope may be suitable for screening early stages of cervical cancer.

True cadence and step accumulation are not equivalent: the effect of intermittent claudication on free-living cadence.

'True cadence' is the rate of stepping during the period of stepping. 'Step accumulation' is the steps within an epoch of time (e.g. 1min). These terms have been used interchangeably in the literature. These outcomes are compared within a population with intermittent claudication (IC). Multiday, 24h stepping activity of those with IC (30) and controls (30) was measured objectively using the activPAL physical activity monitor. 'True cadence' and 'step accumulation' outcomes were calculated. Those with IC took fewer steps/d 6531±2712 than controls 8692±2945 (P=0.003). However, these steps were taken within approximately the same number of minute epochs (IC 301±100min/d; controls 300±70min/d, P=0.894) with only slightly lower true cadence (IC 69 (IQ 66,72) steps/min; controls 72 (IQ 68,76) steps/min, P=0.026), giving substantially lower step accumulation (IC 22 (IQ 19,24) steps/min; controls 30 (IQ 23,34) steps/min) (P<0.001). However, the true cadence of stepping within the blocks of the 1, 5, 20, 30 and 60min with the maximum number of steps accumulated was lower for those with IC than controls (P<0.05). Those with IC took 1300 steps fewer per day above a true cadence of 90 steps/min. True cadence and step accumulation outcomes were radically different for the outcomes examined. 'True cadence' and 'step accumulation' were not equivalent in those with IC or controls. The measurement of true cadence in the population of people with IC provides information about their stepping rate during the time they are stepping. True cadence should be used to correctly describe the rate of stepping as performed.

Subcutaneous Trastuzumab for HER2-positive Breast Cancer - Evidence and Practical Experience in 7 German Centers.

A subcutaneous formulation of trastuzumab to treat patients with HER2-positive breast cancer is available since August 2013. The subcutaneous formulation is administered as a fixed dose of 600 mg over a period of up to 5 minutes. The HannaH trial compared subcutaneous with intravenous administration and found comparable pharmacokinetics, efficacy and tolerability for both administration forms of trastuzumab in the neoadjuvant setting. The randomized crossover study PrefHer reported a clear preference from the patient's point of view for subcutaneous over intravenous administration of trastuzumab. The accompanying time-and-motion study reported a reduction concerning the total time spent for the institution as well as for the patient receiving trastuzumab s. c.. The experience of 7 German centers largely corresponded with the results of these studies. Patients expressed a clear preference for subcutaneous trastuzumab administration, with the time saved by the subcutaneous administration route cited as the greatest benefit. Although the existing reimbursement terms mean that centers will receive a lower remuneration, the centers' overall evaluation of the subcutaneous administration route for trastuzumab was overwhelmingly positive. The greatest benefit cited by the centers was the flexibility in scheduling patient appointments. This increased flexibility improved conditions in some centers which were experiencing pressures due to a shortage of staff, particularly at peak times. The general consensus, however, was that the remuneration systems for oncological treatments urgently need to be amended to ensure that the real costs of treatment are covered, even if the administration route has changed.

Characterisation of the murine gene encoding the intracellular hyaluronan receptor IHABP (RHAMM).

We have recently shown that the published cDNA sequence encoding the murine cell surface receptor for hyaluronan-mediated motility (RHAMM) in fact represents a partial sequence of the cDNA encoding a new intracellular hyaluronic acid binding protein (IHABP). Here we publish the genomic organisation, including 700bp sequences of the promoter region, of the IHABP gene. The IHABP gene consists of 18 exons and spans more than 25kb. Part of the IHABP gene is identical with the published data on RHAMM. The IHABP gene apparently possesses one promoter region with one major transcriptional start point. IHABP is ubiquitously expressed at the mRNA and the protein level in all murine tissues, suggesting that the function of this intracellular hyaluronan binding protein is not restricted to migrating cells.

Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer.

Evidence for a role of ovarian factors in the growth of metastatic breast cancer was first recognized over 100 years ago. Today, anti-estrogens are central to the treatment of breast cancer of all stages. We now understand that the action of estrogen is mediated by the estrogen receptors (ER) which are members of the nuclear receptor family of ligand-regulated transcription factors. In this article we review the molecular mechanisms through which ER activates transcription of target genes and through which available anti-estrogens mediate their therapeutic effects. We discuss possible mechanisms of failure of treatment with current anti-estrogens and how newer anti-estrogens under development attempt to address these problems. In addition an expanded view of the molecular mechanisms of estrogen action is leading to the development of novel selective ER modulators or SERMs.