Estrogen Receptor-Regulated Gene Signatures in Invasive Breast Cancer Cells and Aggressive Breast Tumors.

Most metastatic breast cancers arise from estrogen receptor α (ER)-positive disease, and yet the role of ER in promoting metastasis is unclear. Here, we used an ER+ breast cancer cell line that is highly invasive in an ER- and IKKß-dependent manner. We defined two ER-regulated gene signatures that are specifically regulated in the subpopulations of invasive cells. The first consists of proliferation-associated genes, which is a known function of ER, which actually suppress rather than enhance invasion. The second signature consists of genes involved in essential biological processes, such as organelle assembly and vesicle trafficking. Importantly, the second subpopulation-specific signature is associated with aggressive disease and poor patient outcome, independently of proliferation. These findings indicate a complex interplay between ER-driven proliferation and invasion, and they define new ER-regulated gene signatures that are predictive of aggressive ER+ breast cancer.

Aging well with psychosis.

BACKGROUND AND OBJECTIVES: Despite the unique challenges faced by people living with a severe mental illness, little work has been done to understand how these populations can age well. This study therefore aimed to explore the views of mid to older aged adults living with a psychosis on what it means to age well, and how they might be supported in this endeavor. RESEARCH DESIGN AND METHODS: Semi-structured interviews were conducted with sixteen individuals (age 50-74 years) diagnosed with psychosis-related disorders (e.g. schizophrenia). Inductive thematic analysis was used to analyze the data. RESULTS: Four themes were identified: (i) Engagement with Life - referring to participating in, and maintaining, activities that bring satisfaction and value; (ii) Attitude to Life and Aging - referring to a positive attitude and outlook, and accepting aging-related challenges; (iii) Health and Wellbeing - relating to keeping as physically and mentally fit as possible and (iv) Social Connections - referring to both personal and professional relationships, and feeling heard and understood by others. DISCUSSION AND IMPLICATIONS: Whilst there were clear parallels between these results and those reported from other populations, participants aging with a psychosis revealed challenges, perceptions, and nuances that were unique to their situation. The importance of relationships with professionals, developing a mastery over their mental health difficulties, and the continued impact of stigma on aging well were highlighted. This suggests that approaches that target external societal factors, as well as therapeutic interventions focused on the individual, may help this population to age well.

Update on the Role of NFκB in Promoting Aggressive Phenotypes of Estrogen Receptor-Positive Breast Cancer.

The majority of breast cancers are diagnosed as estrogen receptor-positive (ER+) and respond well to ER-targeted endocrine therapy. Despite the initial treatability of ER+ breast cancer, this subtype still accounts for the majority of deaths. This is partly due to the changing molecular characteristics of tumors as they progress to aggressive, metastatic, and frequently therapy resistant disease. In these advanced tumors, targeting ER alone is often less effective, as other signaling pathways become active, and ER takes on a redundant or divergent role. One signaling pathway whose crosstalk with ER has been widely studied is the nuclear factor kappa B (NFκB) signaling pathway. NFκB is frequently implicated in ER+ tumor progression to an aggressive disease state. Although ER and NFκB frequently co-repress each other, it has emerged that the 2 pathways can positively converge to play a role in promoting endocrine resistance, metastasis, and disease relapse. This will be reviewed here, paying particular attention to new developments in the field. Ultimately, finding targeted therapies that remain effective as tumors progress remains one of the biggest challenges for the successful treatment of ER+ breast cancer. Although early attempts to therapeutically block NFκB activity frequently resulted in systemic toxicity, there are some effective options. The drugs parthenolide and dimethyl fumarate have both been shown to effectively inhibit NFκB, reducing tumor aggressiveness and reversing endocrine therapy resistance. This highlights the need to revisit targeting NFκB in the clinic to potentially improve outcome for patients with ER+ breast cancer.

Cytoplasmic ERα and NFκB Promote Cell Survival in Mouse Mammary Cancer Cell Lines.

There is a desperate need in the field for mouse mammary tumors and cell lines that faithfully mimic estrogen receptor (ER) expression and activity found in human breast cancers. We found that several mouse mammary cancer cell lines express ER but fail to demonstrate classical estrogen-driven proliferation or transcriptional activity. We investigated whether these cell lines may be used to model tamoxifen resistance by using small molecule inhibitors to signaling pathways known to contribute to resistance. We found that the combination of NFκB inhibition and ER antagonists significantly reduced cell proliferation in vitro, as well as growth of syngeneic tumors. Surprisingly, we found that ER was localized to the cytoplasm, regardless of any type of treatment. Based on this, we probed extra-nuclear functions of ER and found that co-inhibition of ER and NFκB led to an increase in oxidative stress and apoptosis. Together, these findings suggest that cytoplasmic ER and NFκB may play redundant roles in protecting mammary cancer cells from oxidative stress and cell death. Although this study has not identified a mouse model with classical ER activity, cytoplasmic ER has been described in a small subset of human breast tumors, suggesting that these findings may be relevant for some breast cancer patients.

A systematic review of the effects of psychosocial interventions on social functioning for middle-aged and older-aged adults with severe mental illness.

OBJECTIVES: The number of older adults with severe mental health problems such as schizophrenia is likely to double in the next 20 years. The needs of this patient group change across the life course, but difficulties with social functioning persist into older age. Poorer social functioning is associated with poorer outcomes and has been identified as a priority for intervention by patients themselves. This paper systematically reviews studies examining the effectiveness of psychosocial interventions on social functioning for people with severe mental health problems in later life. METHODS: A systematic review of peer-reviewed journal articles was conducted and databases were searched from inception to December 2017. The review was limited to psychosocial interventions, for mid to older aged adults (≥40 years of age) with severe mental illness that included a validated measure of social functioning. RESULTS: Fifteen studies (17 papers) met inclusion criteria. There was evidence to support skills training interventions that primarily focused on social skills training or integrated mental and physical health interventions. There was not sufficient evidence to recommend any other interventions. CONCLUSIONS: The results highlight the limited nature of interventions designed specifically for older people with severe mental health problems that target social functioning and the need for more robust, large-scale studies in the area. Current evidence suggests that cognitive behaviour therapy can be effective in targeting social functioning in younger age groups, but, as yet, there is insufficient evidence to recommend this intervention for an older population.

Insights into how phosphorylation of estrogen receptor at serine 305 modulates tamoxifen activity in breast cancer.

Estrogen receptor (ER) is the most important factor in the pathophysiology of breast cancer. Consequently, modulation of ER activity has been exploited to develop drugs against ER + breast cancer, such as tamoxifen, referred to as endocrine therapies. With deeper understanding of ER mechanism of action, posttranslational modifications (PTMs) are increasingly recognized as important in mediating ER activity. Some ER PTMs such as phosphorylation, are studied in the context of ligand-independent ER activity. However, they also play a pivotal role in defining the actions and outcome of the antiestrogen-bound ER. The complexity of these actions is increasing as new PTMs are identified, yet the functional consequences and clinical implications are not fully understood. This review will examine and summarize new emerging mechanistic knowledge and clinical data in breast cancer on how these PTMs affect antiestrogen-ER activity, with an emphasis on phosphorylation of serine 305 (S305). This phosphorylation site represents an integrated hub of oncogenic signaling to modulate ER conformation, dimerization, coregulators, and DNA binding to profoundly reduce sensitivity to endocrine therapy. Consequently, (i) S305 has the potential to become a useful marker of tamoxifen response, and (ii) blocking S305 phosphorylation defines a new therapeutic strategy to overcome tamoxifen resistance in breast cancer.

An Evaluation of Matrix-Containing and Humanised Matrix-Free 3-Dimensional Cell Culture Systems for Studying Breast Cancer.

BACKGROUND: 3D cell cultures are emerging as more physiologically meaningful alternatives to monolayer cultures for many biological applications. They are attractive because they more closely mimic in vivo morphology, especially when co-cultured with stromal fibroblasts. METHODOLOGY/PRINCIPAL FINDINGS: We compared the efficacy of 3 different 3D cell culture systems; collagen I, low attachment culture vessels and a modification of Fibrolife®, a specialised humanised cell culture medium devoid of animal-derived components, using breast cancer cell lines representative of the different molecular subtypes of breast cancer, cultured alone or with human mammary fibroblasts with a view to developing matrix-free humanised systems. 3D collagen I culture supported the growth of a range of breast cancer cell lines. By modifying the composition of Fibrolife® to epiFL, matrix-free cell culture was possible. During sequential transfer to epiFL breast cancer cells gradually detached from the flask, growing progressively as spheroids. Phenotype was stable and reversible with cells remaining actively proliferating and easily accessible throughout culture. They could also be revived from frozen stocks. To achieve co-culture with fibroblasts in epiFL required use of low attachment culture vessels instead of standard plastic as fibroblasts remained adherent in epiFL. Here, cancer cell spheroids were allowed to form before adding fibroblasts. Immunohistochemical examination showed fibroblasts scattered throughout the epithelial spheroid, not dissimilar to the relationship of tumour stroma in human breast cancer. CONCLUSIONS: Because of its ease of handling, matrix-free 3D cell culture may be a useful model to study the influence of fibroblasts on breast cancer epithelial cells with use of epiFL culture medium taking this a step further towards a fully humanised 3D model. This methodology could be applied to other types of cancer cell lines, making this a versatile technique for cancer researchers wishing to use in vitro systems that better reflect cancer in vivo.

Occupational complexity and lifetime cognitive abilities.

OBJECTIVE: To examine associations between complexity of main lifetime occupation and cognitive performance in later life. METHODS: Occupational complexity ratings for data, people, and things were collected from the Dictionary of Occupational Titles for 1,066 individuals (men = 534, women = 532) in the Lothian Birth Cohort 1936. IQ data were available from mean age 11 years. Cognitive ability data across the domains of general ability, processing speed, and memory were available at mean age 70 years. RESULTS: General linear model analyses indicated that complexity of work with people and data were associated with better cognitive performance at age 70, after including age 11 IQ, years of education, and social deprivation. CONCLUSIONS: The current findings are supportive of the differential preservation hypotheses that more stimulating environments preserve cognitive ability in later life, although the continued effects into old age are still debated. Studies that have early-life cognitive ability measures are rare, and the current study offers interesting prospects for future research that may further the understanding of successful aging.

Estrogen receptor ß: putting a positive into triple negative breast cancer?

Abstract ERß was discovered over 15 years ago, yet the initial expectancy that this protein could have therapeutic use has ebbed, because of the complexity surrounding its function and significance in breast cancer. It has become apparent that its functional role and prognostic significance in breast cancer may depend on a number of factors, such as co-expression with ERα, presence of various isoforms (ERß1, -2 and -5 in breast cancer), post-transcriptional modifications and cellular location. Interestingly, ERß1 is often expressed in triple negative breast cancer (TNBC), a more aggressive type of breast cancer with limited treatment options because of the lack of expression of a recognised biological target. Furthermore, clinical data has demonstrated a clear correlation between ERß1 positivity and improved disease-free and overall survival in those patients treated with tamoxifen. This suggests ERß1 may be worth considering as a potential therapeutic target, particularly in TNBC.