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OBJECTIVES Mitochondrial DNA (mtDNA) heteroplasmy is a mixture of normal and mutated mtDNA molecules in a cell. High levels of heteroplasmy at several mtDNA sites in complex I lead to inherited neurological neurologic diseases and brain magnetic resonance imaging (MRI) abnormalities. Here, we test the hypothesis that mtDNA heteroplasmy at these complex I sites is associated with depressive symptoms in the elderly. METHODS We examined platelet mtDNA heteroplasmy for associations with depressive symptoms among 137 participants over age 70 from the community-based Health, Aging and Body Composition Study. Depressive symptoms were assessed using the 10-point version of the Center for Epidemiologic Studies Depression Scale (CES-D 10). Complete mtDNA sequencing was performed and heteroplasmy derived for 5 mtDNA sites associated with neurologic mitochondrial diseases and tested for associations with depressive symptoms. RESULTS Of 5 candidate complex I mtDNA mutations examined for effects on depressive symptoms, increased heteroplasmy at m.13514A>G, ND5, was significantly associated with higher CES-D score (P = .01). A statistically significant interaction between m.13514A > G heteroplasmy and sex was detected (P = .04); in sex-stratified analyses, the impact of m.13514A>G heteroplasmy was stronger in male (P = .003) than in female (P = .98) participants. Men in highest tertile of mtDNA heteroplasmy exhibited significantly higher (P = .0001) mean ± SE CES-D 10 scores, 5.37 ± 0.58, when compared with those in the middle, 2.13 ± 0.52, and lowest tertiles, 2.47 ± 0.58. No associations between the 4 other candidate sites and depressive symptoms were observed. CONCLUSIONS Increased mtDNA heteroplasmy at m.13514A>G is associated with depressive symptoms in older men. Heteroplasmy may represent a novel biological risk factor for depression.

Background Depressive symptoms are common in older adults and associated with poor outcomes. Although circadian genes have been implicated in depression, the relationship between circadian genes and depressive symptoms in older adults is unclear. Methods A cross-sectional genetic association study of 529 single nucleotide polymorphisms (SNPs) representing 30 candidate circadian genes was performed in two population-based cohorts: the Osteoporotic Fractures in Men Study (MrOS; N = 270, age: 76.58 ± 5.61 years) and the Study of Osteoporotic Fractures (SOF) in women (N = 1740, 84.05 ± 3.53 years) and a meta-analysis was performed. Depressive symptoms were assessed with the Geriatric Depression Scale categorizing participants as having none-few symptoms (0–2), some depressive symptoms (>2 to Results We found associations meeting multiple testing criteria for significance between the PER3 intronic SNP rs12137927 and decreased odds of reporting "some depressive symptoms" in the SOF sample (odds ratio [OR]: 0.61, 95% confidence interval [CI]: 0.48–0.78, df = 1, Wald χ 2 = −4.04, p = 0.000054) and the meta-analysis (OR: 0.61, CI: 0.48–0.78, z = –4.04, p = 0.000054) and between the PER3 intronic SNPs rs228644 (OR: 0.74, CI: 0.63–0.86, z = 3.82, p = 0.00013) and rs228682 (OR: 0.74, CI: 0.86–0.63, z = 3.81, p = 0.00014) and decreased odds of reporting "some depressive symptoms" in the meta-analysis compared to endorsing none–few depressive symptoms. The RORA intronic SNP rs11632098 was associated with greater odds of reporting "many depressive symptoms" (OR: 2.16, CI: 1.45–3.23, df = 1, Wald χ 2 = 3.76, p = 0.000168) in the men. In the meta-analysis the association was attenuated and nominally significant (OR: 1.63, CI: 1.24–2.16, z = 3.45, p = 0.00056). Conclusion PER3 and RORA may play important roles in the development of depressive symptoms in older adults.

OBJECTIVE To investigate the longitudinal relationship between subjective and objective sleep disturbance and depressive symptoms. DESIGN Longitudinal. SETTING Three US clinical centers. PARTICIPANTS Nine hundred fifty-two community-dwelling older women (70 y or older). MEASUREMENTS At baseline, subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) and objective sleep measures were assessed with wrist actigraphy. Depressive symptoms were assessed with the Geriatric Depression Scale (GDS) at baseline and approximately 5 y later. The analysis was restricted to women with few (GDS 0-2) depressive symptoms at baseline. RESULTS There was an independent association between greater PSQI score (per standard deviation increase, indicating worse subjective sleep quality) at baseline and greater odds of worsening depressive symptoms (≥ 2-point increase in GDS) (Multivariate Odds Ratio [MOR] 1.19, confidence interval [CI] 1.01-1.40, P = 0.036). Higher scores specifically on the sleep quality (MOR 1.41, CI 1.13-1.77, P < 0.003) and sleep latency (MOR 1.21, CI 1.03-1.41, P = 0.018) PSQI subscales were also associated with greater odds for worsening depressive symptoms. Objective assessments revealed an association between baseline prolonged wake after sleep onset (WASO ≥ 60 min) and worsening depressive symptoms at follow-up (MOR 1.36, CI 1.01-1.84, P = 0.046). There were no associations between other objectively assessed sleep measures and worsening depressive symptoms. CONCLUSIONS In older women with few or no depressive symptoms at baseline, those with more subjectively reported sleep disturbance and more objectively assessed fragmentation of sleep at baseline had greater odds of worsening depressive symptoms 5 y later. Future studies investigating this relationship in more detail are indicated. CITATION Maglione JE, Ancoli-Israel S, Peters KW, Paudel ML, Yaffe K, Ensrud KE, Stone KL, Study of Osteoporotic Fractures Research Group. Subjective and objective sleep disturbance and longitudinal risk of depression in a cohort of older women.

Sleep disturbance, fatigue and depression are common complaints in patients with cancer, and often contribute to worse quality of life (QoL). Circadian activity rhythms (CARs) are often disrupted in cancer patients. These symptoms worsen during treatment, but less is known about their long-term trajectory.Sixty-eight women with stage I-III breast cancer (BC) scheduled to receive ≥4 cycles of chemotherapy, and age-, ethnicity-, and education-matched normal, cancer-free controls (NC) participated. Sleep was measured with actigraphy (nocturnal total sleep time [nocturnal TST] and daytime total nap time [NAPTIME]) and with the Pittsburgh Sleep Quality Index (PSQI); fatigue with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF); depression with the Center of Epidemiological Studies-Depression (CES-D). CARs were derived from actigraphy. Several measures of QoL were administered. Data were collected at three time points: before (baseline), end of cycle 4 (cycle 4), and 1 year post-chemotherapy (1 year).Compared to NC, BC had longer NAPTIME, worse sleep quality, more fatigue, more depressive symptoms, more disrupted CARs, and worse QoL at baseline (all p values0.05). At cycle 4, BC showed worse sleep, increased fatigue, more depressive symptoms, and more disrupted CARs compared to their own baseline levels and to NC (all p values0.05). By 1 year, BC's fatigue, depressive symptoms, and QoL returned to baseline levels but were still worse than those of NC, while NAPTIME and CARs did not differ from NC's.Additional research is needed to determine if beginning treatment of these symptoms before the start of chemotherapy will minimize symptom severity over time.

Author(s): Neikrug, Ariel B; Liu, Lianqi; Avanzino, Julie A; Maglione, Jeanne E; Natarajan, Loki; Bradley, Lenette; Maugeri, Alex; Corey-Bloom, Jody; Palmer, Barton W; Loredo, Jose S; Ancoli-Israel, Sonia | Abstract: Study objectivesObstructive sleep apnea (OSA), common in Parkinson disease (PD), contributes to sleep disturbances and daytime sleepiness. We assessed the effect of continuous positive airway pressure (CPAP) on OSA, sleep, and daytime sleepiness in patients with PD.DesignThis was a randomized placebo-controlled, crossover design. Patients with PD and OSA were randomized into 6 w of therapeutic treatment or 3 w of placebo followed by 3 w of therapeutic treatment. Patients were evaluated by polysomnography (PSG) and multiple sleep latency test (MSLT) pretreatment (baseline), after 3 w, and after 6 w of CPAP treatment. Analyses included mixed models, paired analysis, and within-group analyses comparing 3 w to 6 w of treatment.SettingSleep laboratory.ParticipantsThirty-eight patients with PD (mean age = 67.2 ± 9.2 y; 12 females).InterventionContinuous positive airway pressure.MeasurementsPSG OUTCOME MEASURES: sleep efficiency, %sleep stages (N1, N2, N3, R), arousal index, apnea-hypopnea index (AHI), and % time oxygen saturation l 90% (%time SaO2 l 90%). MSLT outcome measures: mean sleep-onset latency (MSL).ResultsThere were significant group-by-time interactions for AHI (P l 0.001), % time SaO2 l 90% (P = 0.02), %N2 (P = 0.015) and %N3 (P = 0.014). Subjects receiving therapeutic CPAP showed significant decrease in AHI, %time SaO2 l 90%, %N2, and significant increase in %N3 indicating effectiveness of CPAP in the treatment of OSA, improvement in nighttime oxygenation, and in deepening sleep. The paired sample analyses revealed that 3 w of therapeutic treatment resulted in significant decreases in arousal index (t = 3.4, P = 0.002). All improvements after 3 w were maintained at 6 w. Finally, 3 w of therapeutic CPAP also resulted in overall decreases in daytime sleepiness (P = 0.011).ConclusionsTherapeutic continuous positive airway pressure versus placebo was effective in reducing apnea events, improving oxygen saturation, and deepening sleep in patients with Parkinson disease and obstructive sleep apnea. Additionally, arousal index was reduced and effects were maintained at 6 weeks. Finally, 3 weeks of continuous positive airway pressure treatment resulted in reduced daytime sleepiness measured by multiple sleep latency test. These results emphasize the importance of identifying and treating obstructive sleep apnea in patients with Parkinson disease.

Objective Obstructive sleep apnea (OSA) is very common in Parkinson's disease (PD). OSA is known to affect patients' cognition. The present study assessed whether PD patients with OSA (PD + OSA) score lower on cognitive measures than those without OSA (PD − OSA). In addition, this study evaluated whether treating the OSA with continuous positive airway pressure (CPAP) in PD + OSA patients results in an improved cognitive functioning. Methods Eighty-six patients with PD underwent an overnight polysomnography screen for OSA and were administered the Mini-Mental Status Exam (MMSE) and the Montreal Cognitive Assessment (MoCA). This resulted in 38 patients with PD + OSA who were randomly assigned to receive either therapeutic CPAP for 6 weeks ( n = 19) or placebo CPAP for three weeks followed by therapeutic CPAP for three weeks ( n = 19). Intervention participants completed a neurocognitive battery at baseline and 3- and 6-week time-points. Results Patients with PD + OSA scored significantly lower than PD − OSA on the MMSE and MoCA after controlling for age, education, and PD severity. OSA was a significant predictor of cognition (MMSE p 0.01; MoCA p = 0.028).There were no significant changes between groups in cognition when comparing three weeks of therapeutic CPAP with 3 weeks of placebo CPAP. Comparisons between pre-treatment and 3-week post-therapeutic CPAP for the entire sample also revealed no significant changes on overall neuropsychological (NP) scores. Conclusions Findings suggest that PD patients with OSA show worse cognitive functioning on cognitive screening measures than those without OSA. However, OSA treatment after three or six weeks of CPAP may not result in overall cognitive improvement in patients with PD.

To examine the relationship between depressive symptoms and subjective and objective sleep in older women.Cross-sectional.Four U.S. clinical centers.Three thousand forty-five community-dwelling women aged 70 and older.Depressive symptoms were assessed using the Geriatric Depression Scale, categorizing participants as normal (0-2, reference), some depressive symptoms (3-5), or depressed (≥ 6). Subjective sleep quality and daytime sleepiness were assessed using the Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Objective sleep measures were assessed using wrist actigraphy.In multivariable-adjusted models, there were graded associations between greater level of depressive symptoms and worse subjective sleep quality and more subjective daytime sleepiness (P-trends.001). Women with some depressive symptoms (odds ratio (OR) = 1.82, 95% confidence interval (CI) = 1.48-2.24) and depressed (OR = 2.84, 95% CI = 2.08-3.86) women had greater odds of reporting poor sleep (PSQI5). Women with some depressive symptoms (OR = 1.97, 95% CI = 1.47-2.64) and depressed women (OR = 1.70, 95% CI = 1.12-2.58) had greater odds of reporting excessive daytime sleepiness (ESS10). There were also graded associations between greater level of depressive symptoms and objectively measured wake after sleep onset (WASO) (P-trend = .03) and wake episodes longer than 5 minutes (P-trend = .006). Depressed women had modestly higher odds of WASO of 1 hour or longer (OR = 1.37, 95% CI = 1.03-1.83). Women with some depressive symptoms (OR = 1.49, 95% CI = 1.19-1.86) and depressed women (OR = 2.04, 95% CI = 1.52-2.74) had greater odds of being in the highest quartile for number of nap episodes longer than 5 minutes. No associations between depressive symptom level and prolonged sleep latency, poor sleep efficiency, or short or long total sleep time were found.Greater depressive symptom levels were associated with more subjective sleep disturbance and objective evidence of sleep fragmentation and napping.

Major depression is prevalent, difficult to assess, underrecognized, and undertreated in hospice settings. Furthermore, it is associated with significant morbidity and mortality. A retrospective chart review of 2716 patients receiving hospice care was conducted in order to determine the baseline rate of recognition of depression in patients with advanced, life-threatening illnesses by frontline hospice clinicians. Documentation of "depression" as either a diagnosis or problem was used as an estimate of how often these disorders were considered significant issues by the treating interdisciplinary team. Of the patients receiving home/long-term care, 10.8% (234/2168) had depression documented as a diagnosis or significant problem. The presence of recognized depression in this setting was associated with significant differences in gender, marital status, and terminal diagnoses. Total length of hospice care was also significantly longer. Of patients receiving inpatient care, 13.7% (75/548) had depression documented as a diagnosis or significant problem. Recognized depression in this setting was associated with significant differences in marital status, length of inpatient stay, and total time in hospice care. If documentation is representative of the care that the interdisciplinary teams provide, depression of any kind appears to be underrecognized in this population. In fact, it is on the low end of prevalence estimates in the literature. Improved depression assessment is needed in order to minimize the impact of depression on patients living with advanced, life-threatening illnesses.

© 2014, Springer Science+Business Media New York.Depression adversely predicts prognosis in individuals with symptomatic heart failure. In some clinical populations, spiritual wellness is considered to be a protective factor against depressive symptoms. This study examined associations among depressive symptoms, spiritual wellbeing, sleep, fatigue, functional capacity, and inflammatory biomarkers in 132 men and women with asymptomatic stage B heart failure (age 66.5 years ± 10.5). Approximately 32 % of the patients scored ≥10 on the Beck Depression Inventory, indicating potentially clinically relevant depressive symptoms. Multiple regression analysis predicting fewer depressive symptoms included the following significant variables: a lower inflammatory score comprised of disease-relevant biomarkers (p

Nitric oxide (NO) and its metabolites are implicated in carcinogenesis and metastasis. Both stimulatory and inhibitory effects of NO have been reported in relation to breast cancer and its role in the development of malignancies and metastasis remains uncertain. We have used the polyomavirus middle T antigen (PyV-mT) targeted to the mouse mammary gland and bred into an inducible NO synthase (iNOS)deficient C57Bl/6 strain to examine a role for nitric oxide in modulating tumors that develop in the complex environment of the whole animal. The development of hyperplasias was delayed to the extent that the earliest palpable tumors arose 2– 4 weeks later in PyV-mT/iNOS / mice compared with PyV-mT/iNOS / mice, identifying a role for iNOS in early events in mammary tumor formation. Tumors that did develop in PyV-mT/iNOS / mice were characteristically well differentiated and had a cribriform pattern. Other tumors were myoepithelial adenocarcinomas with uniform nuclear size. In contrast, mice capable of iNOS activity typically developed solid nodular adenocarcinomas with a high mitotic index and pleomorphic nuclei. No significant effect of iNOS deficiency was found on vascular density in hyperplasias or tumors by examining CD31-positive vessels. The infiltration of lesions by macrophages, cells capable of significant NO production, remained unchanged in PyV-mT/iNOS / mice. Metastatic potential was retained by PyV-mT-transformed epithelium in the absence of iNOS, indicating that NO production by iNOS is not essential for this process. These results indicate a role for iNOS in tumorigenesis, particularly in the regulation of early events. © 2003 Wiley-Liss, Inc.

Objective: Rapid eye movement (REM)-sleep behavior disorder (RBD) is often comorbid with Parkinson's disease (PD). The current study aimed to provide a detailed understanding of the impact of having RBD on multiple non-motor symptoms (NMS) in patients with PD. Methods: A total of 86 participants were evaluated for RBD and assessed for multiple NMS of PD. Principal component analysis was utilized to model multiple measures of NMS in PD, and a multivariate analysis of variance was used to assess the relationship between RBD and the multiple NMS measures. Seven NMS measures were assessed: cognition, quality of life, fatigue, sleepiness, overall sleep, mood, and overall NMS of PD. Results: Among the PD patients, 36 were classified as having RBD (objective polysomnography and subjective findings), 26 as not having RBD (neither objective nor subjective findings), and 24 as probably having RBD (either subjective or objective findings). RBD was a significant predictor of increased NMS in PD while controlling for dopaminergic therapy and age (p = 0.01). The RBD group reported more NMS of depression (p = 0.012), fatigue (p = 0.036), overall sleep (p = 0.018), and overall NMS (p = 0.002). Conclusion: In PD, RBD is associated with more NMS, particularly increased depressive symptoms, sleep disturbances, and fatigue. More research is needed to assess whether PD patients with RBD represent a subtype of PD with different disease progression and phenomenological presentation. © 2014 Elsevier B.V. All rights reserved.

Author(s): Maglione, Jeanne E; Liu, Lianqi; Neikrug, Ariel B; Poon, Tina; Natarajan, Loki; Calderon, Joanna; Avanzino, Julie A; Corey-Bloom, Jody; Palmer, Barton W; Loredo, Jose S; Ancoli-Israel, Sonia | Abstract: ObjectivesTo assess the usefulness of actigraphy for assessment of nighttime sleep measures in patients with Parkinson's disease (PD).DesignParticipants underwent overnight sleep assessment simultaneously by polysomnography (PSG) and actigraphy.SettingOvernight sleep study in academic sleep research laboratory.ParticipantsSixty-one patients (mean age 67.74 ± 8.88 y) with mild to moderate PD.MeasurementsSleep measures including total sleep time (TST), sleep efficiency (SE), wake after sleep onset (WASO), and sleep onset latency (SOL) were calculated independently from data derived from PSG and from actigraphy. Different actigraphy scoring settings were compared.ResultsNo single tested actigraphy scoring setting was optimal for all sleep measures. A customized setting of an activity threshold of 10, with five consecutive immobile minutes for sleep onset, yielded the combination of mean TST, SE, and WASO values that best approximated mean values determined by PSG with differences of 6.05 ± 85.67 min for TST, 1.1 ± 0.641% for SE, and 4.35 ± 59.56 min for WASO. There were significant but moderate correlations between actigraphy and PSG measurements (rs = 0.496, P l 0.001 for TST, rs = 0.384, P = 0.002 for SE, and rs = 0.400, P = 0.001 for WASO) using these settings. Greater disease stage was associated with greater differences between TST (R(2) = 0.099, beta = 0.315, P = 0.018), SE (R(2) = 0.107, beta = 0.327, P = 0.014), and WASO (R(2) = 0.094, beta = 0.307, P = 0.021) values derived by actigraphy and PSG explaining some of the variability. Using a setting of 10 immobile min for sleep onset yielded a mean SOL that was within 1 min of that estimated by PSG. However SOL values determined by actigraphy and PSG were not significantly correlated at any tested setting.ConclusionsOur results suggest that actigraphy may be useful for measurement of mean TST, SE, and WASO values in groups of patients with mild to moderate Parkinson's disease. However, there is a significant degree of variability in accuracy among individual patients. The importance of determining optimal scoring parameters for each population studied is underscored.

Background The aim of the present study was to explore the association between Parkinson's disease (PD) clinical characteristics and cardiac autonomic control across sleep stages. Methods Frequency-domain heart rate variability (HRV) measures were estimated in 18 PD patients undergoing a night of polysomnography. Results Significant relationships were found between PD severity and nocturnal HRV indices. The associations were restricted to rapid eye movement (R) sleep. Conclusions The progressive nocturnal cardiac autonomic impairment occurring with more severe PD can be subclinical emerging only during conditions requiring active modulation of physiological functions such as R-sleep.

ObjectivesAging is associated with changes in circadian rhythms. Current evidence supports a role for circadian rhythms in the pathophysiology of depression. However, little is known about the relationship between depressive symptoms and circadian activity rhythms in older adults. We examined this association in community-dwelling older women.MethodsWe performed a cross-sectional analysis of 3,020 women (mean age: 83.55 ± 3.79 years) enrolled in the Study of Osteoporotic Fractures. Depressive symptoms were assessed with the Geriatric Depression Scale categorizing participants as "normal" (0-2; referent group, N= 1,961), "some depressive symptoms" (3-5, N= 704), or "depressed" (≥6, N= 355). Circadian activity rhythm variables were measured using wrist actigraphy.ResultsIn age-adjusted and Study of Osteoporotic Fractures site-adjusted models, greater levels of depressive symptoms were associated with decreased amplitude (height; df= 3,014, t=-11.31, p for linear trend&nbsp

Objective The aim of the current study was to investigate the frequency of periodic limb movements in sleep (PLMS) in Parkinson's disease (PD) and their impact on nocturnal sleep and daytime functioning. Methods Forty-five PD patients (mean age 68.5 ± 8.7 years; 32 males) underwent one night of polysomnography (PSG). Clinical assessment and questionnaires evaluating sleep disturbance and quality of life (QoL) were completed. Patients were divided into two groups based on their PLMS index (PLMSI): PLMSI ≥ 15 (PLMS +) and PLMSI Results There were 26 (57.8%) PD patients in the PLMS + group and 19 (42.2%) patients in the PLMS − group. Subjective assessment revealed an association between PLMS + status and greater PD symptom severity, more subjective sleep disturbance, and decreased QoL. All patients showed poor sleep, and no significant group differences were detected on PSG measures. Conclusion We observed that PLMS occurred frequently in PD and increased with more severe PD. Although PLMS did not affect objective sleep, it was associated with increased sleep complaints and reduced QoL. Overall, our findings support the association between PLMS and PD as well as the clinical relevance of sleep disturbances in PD.

Objectives:Delirium is prevalent, difficult to assess, under-recognized, and undertreated in hospice and palliative care settings. Furthermore, it is associated with significant morbidity and mortality. Under-recognition of delirium results in under-treatment and increased suffering. The intent of this study was to retrospectively evaluate the recognition of delirium in a large cohort of hospice patients by interdisciplinary hospice care teams.Methods:A retrospective chart review of 2,716 patients receiving hospice care was conducted in order to determine the baseline rate of recognition of delirium in patients with advanced, life-threatening illnesses by front-line hospice clinicians. Documentation of “delirium” as either a diagnosis or problem was used as an estimate of how often these disorders were considered significant issues by the treating interdisciplinary team.Results:Of the patients receiving home/long-term care, 17.8% (386/2168) had delirium documented as a diagnosis or significant problem. The presence of recognized delirium in this setting was associated with significant differences in marital status, ethnicity, hospice diagnosis, and age. Total length of hospice care was also significantly longer. Of patients receiving inpatient care, 28.3% (614/548) had delirium documented as a diagnosis or significant problem. Recognized delirium in this setting was associated with significant differences in gender, ethnicity, hospice diagnosis, and length of inpatient stay.Significance of results:If documentation is representative of the care that the interdisciplinary teams provide, delirium of any kind appears to be under-recognized in this population. In fact, it is on the low end of prevalence estimates in the literature. Improved delirium assessment is needed in order to minimize the impact of delirium on patients living with advanced, life-threatening illnesses and their caregivers.

BackgroundHuman breast cancer is a heterogeneous disease, histopathologically, molecularly and phenotypically. The molecular basis of this heterogeneity is not well understood. We have used a mouse model of DCIS that consists of unique lines of mammary intraepithelial neoplasia (MIN) outgrowths, the premalignant lesion in the mouse that progress to invasive carcinoma, to understand the molecular changes that are characteristic to certain phenotypes. Each MIN-O line has distinguishable morphologies, metastatic potentials and estrogen dependencies.MethodsWe utilized oligonucleotide expression arrays and high resolution array comparative genomic hybridization (aCGH) to investigate whole genome expression patterns and whole genome aberrations in both the MIN-O and tumor from four different MIN-O lines that each have different phenotypes. From the whole genome analysis at 35 kb resolution, we found that chromosome 1, 2, 10, and 11 were frequently associated with whole chromosome gains in the MIN-Os. In particular, two MIN-O lines had the majority of the chromosome gains. Although we did not find any whole chromosome loss, we identified 3 recurring chromosome losses (2F1-2, 3E4, 17E2) and two chromosome copy number gains on chromosome 11. These interstitial deletions and duplications were verified with a custom made array designed to interrogate the specific regions at approximately 550 bp resolution.ResultsWe demonstrated that expression and genomic changes are present in the early premalignant lesions and that these molecular profiles can be correlated to phenotype (metastasis and estrogen responsiveness). We also identified expression changes associated with genomic instability. Progression to invasive carcinoma was associated with few additional changes in gene expression and genomic organization. Therefore, in the MIN-O mice, early premalignant lesions have the major molecular and genetic changes required and these changes have important phenotypic significance. In contrast, the changes that occur in the transition to invasive carcinoma are subtle, with few consistent changes and no association with phenotype.ConclusionWe propose that the early lesions carry the important genetic changes that reflect the major phenotypic information, while additional genetic changes that accumulate in the invasive carcinoma are less associated with the overall phenotype.

Introduction Ductal carcinoma in situ (DCIS) is a noninvasive premalignant lesion and is considered a precursor to invasive carcinoma. DCIS accounts for nearly 20% of newly diagnosed breast cancer, but the lack of experimentally amenable in vivo DCIS models hinders the development of treatment strategies. Here, we demonstrate the utility of a mouse transplantation model of DCIS for chemoprevention studies using selective estrogen receptor modulators (SERMs). This model consists of a set of serially transplanted lines of genetically engineered mouse mammary intraepithelial neoplasia (MIN) outgrowth (MIN-O) tissue that have stable characteristics. We studied the ovarian-hormone-responsiveness of one of the lines with a particular focus on the effects of two related SERMs, tamoxifen and ospemifene. Methods The estrogen receptor (ER) status and ovarian-hormone-dependence of the mouse MIN outgrowth tissue were determined by immunohistochemistry and ovarian ablation. The effects of tamoxifen and ospemifene on the growth and tumorigenesis of MIN outgrowth were assessed at 3 and 10 weeks after transplantation. The effects on ER status, cell proliferation, and apoptosis were studied with immunohistochemistry. Results The MIN-O was ER-positive and ovarian ablation resulted in reduced MIN-O growth and tumor development. Likewise, tamoxifen and ospemifene treatments decreased the MIN growth and tumor incidence in comparison with the control (P < 0.01). Both SERMs significantly decreased cell proliferation. Between the two SERM treatment groups, there were no statistically significant differences in MIN-O size, tumor latency, or proliferation rate. In contrast, the ospemifene treatment significantly increased ER levels while tamoxifen significantly decreased them. Conclusion Tamoxifen and ospemifene inhibit the growth of premalignant mammary lesions and the progression to invasive carcinoma in a transplantable mouse model of DCIS. The inhibitory effects of these two SERMs are similar except for their effects on ER modulation. These differences in ER modulation may suggest different mechanisms of action between the two related SERMs and may portend different long-term outcomes. These data demonstrate the value of this model system for preclinical testing of antiestrogen or other therapies designed to prevent or delay the malignant transformation of premalignant mammary lesions in chemoprevention.

A transplantable model of human ductal carcinoma in situ that progresses to invasive carcinoma was developed from a genetically engineered mouse (GEM). Additional lines were established using early mammary premalignant lesions from transgenic MMTV-PyV-mT mice. These lines were verified to be premalignant and transplanted repeatedly to establish stable and predictable properties. Here, we report the first in-depth molecular analysis of neoplastic progression occurring in one premalignant transplantable GEM-derived line. Oligonucleotide microarrays showed that many genes are differentially expressed between the quiescent and prelactating mammary gland and the premalignant GEM outgrowth. In contrast, a small but consistent group of genes was associated with the transformation from premalignancy to tumor. This suggests that the majority of gene expression changes occur during the premalignant transition from normal to premalignancy, whereas many fewer changes occur during the malignant transition from premalignancy to invasive carcinoma. The premalignant transition is associated with several cell cycle-related genes and the up-regulation of oncogenes is associated with various cancers (Ccnd11, Cdk4, Myb, and Ect2). The changes identified in the malignant transition included genes previously associated with human breast cancer progression. Misregulation of the insulin-like growth factor and transforming growth factor-beta signaling pathways and the stromal-epithelial interaction were implicated. Our results suggest that this transplantable GEM-based model recapitulates human ductal carcinoma in situ at both histologic and molecular levels. With consistent tumor latency and molecular profiles, this model provides an experimental platform that can be used to assess functional genomics and molecular pharmacology and to test promising chemoprevention strategies.