The role of RNA processing and regulation in metastatic dormancy.

Tumor dormancy is a major contributor to the lethality of metastatic disease, especially for cancer patients who develop metastases years-to-decades after initial diagnosis. Indeed, tumor cells can disseminate during early disease stages and persist in new microenvironments at distal sites for months, years, or even decades before initiating metastatic outgrowth. This delay between primary tumor remission and metastatic relapse is known as "dormancy," during which disseminated tumor cells (DTCs) acquire quiescent states in response to intrinsic (i.e., cellular) and extrinsic (i.e., microenvironmental) signals. Maintaining dormancy-associated phenotypes requires DTCs to activate transcriptional, translational, and post-translational mechanisms that engender cellular plasticity. RNA processing is emerging as an essential facet of cellular plasticity, particularly with respect to the initiation, maintenance, and reversal of dormancy-associated phenotypes. Moreover, dysregulated RNA processing, particularly that associated with alternative RNA splicing and expression of noncoding RNAs (ncRNAs), can occur in DTCs to mediate intrinsic and extrinsic metastatic dormancy. Here we review the pathophysiological impact of alternative RNA splicing and ncRNAs in promoting metastatic dormancy and disease recurrence in human cancers.

Smoking and Tobacco-Free Policies in Women's Residential Substance Use Disorder Treatment Facilities: A Community-Engaged Approach.

Introduction: The purpose of this study was to (1) describe the role of smoking in the lives of women in residential substance use disorder (SUD) treatment and (2) explore perceptions of the facilitators and barriers to tobacco-free policy among women in residential SUD treatment. Methods: This was a community-engaged study using qualitative descriptive methods. We first recruited women in a residential SUD treatment facility to participate on a community research team. Interviews with staff (N = 10) and focus groups with clients (N = 42) were conducted using guides informed by the community research team. Interviews and focus groups were analyzed using content analysis. Results: There were two themes related to the role of smoking in the women's lives: (1) smoking facilitates socialization and (2) smoking as a coping mechanism. There were three themes related to the benefits of tobacco-free policy: (1) improved health, (2) support for continued abstinence from a previous tobacco-free placement (eg, prison), and (3) less grounds up-keep. Barriers to tobacco-free policy included (1) lack of an alternative coping mechanism to smoking, (2) fear that a tobacco-free policy would drive clients away, and (3) anticipation of implementation challenges. Conclusions: Many women in residential SUD treatment smoke, which they attribute to the fact that smoking is used to facilitate socialization and cope with stress. Future research is needed to develop and test messages to counter the misperception that smoking is an effective method to cope with stress. Ultimately, evidence-based tobacco-free policies are needed to reduce tobacco-related disease among women with SUDs. Implications: To promote smoking cessation among women with substance use disorders through evidence-based tobacco policy, it is necessary to first understand the role of smoking in their lives as well as facilitators and barriers to tobacco-free policy in residential treatment facilities. Participants reported that smoking facilitated socialization and served as a coping mechanism. Tobacco-free policies have many benefits, including improved health, support for continued abstinence from a previous tobacco-free placement (eg, prison), and less grounds up-keep. Barriers include the lack of an alternative coping mechanism, fear that a tobacco-free policy would drive away clients and anticipation of implementation challenges. To reduce the burden of tobacco-related morbidity and mortality among women and their children, it is necessary to catalyze a culture change in behavioral health settings to prioritize the treatment of tobacco alongside treatment of other addictions.

Inoculation's efficacy with young adults' risky behaviors: can inoculation confer cross-protection over related but untreated issues?

This investigation examined the potential of inoculation to protect young adults' attitudes from pressures to engage in risky behaviors (unprotected sex and binge drinking) as well as inoculation's efficacy in conferring umbrella protection (cross-protection) over related, but experimentally untreated, attitudes. A three-phase experiment was conducted involving 120 participants. The results revealed that inoculation can protect the attitudes of young adults from counterattitudinal pressures to engage in unprotected sex (treated issue) and binge drinking (untreated issue). Practical applications of these findings are explored, including the use of inoculation when designing health messages and more thorough assessments of health campaigns designed to discourage risky behaviors.

lncRNA BORG:TRIM28 Complexes Drive Metastatic Progression by Inducing α6 Integrin/CD49f Expression in Breast Cancer Stem Cells.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with its aggressive phenotype being attributed to chemotherapy resistance, metastatic dissemination, and rapid disease recurrence. Breast cancer stem cells (BCSC) are significant contributors to tumor initiation, as well as to the acquisition of aggressive tumorigenic phenotypes, namely due to their ability to self-replicate and to produce heterogeneous differentiated tumor cells. To elucidate the underlying mechanisms that drive BCSC tumorigenicity in TNBC, we identified the long noncoding RNA (lncRNA) B MP/ O P- R esponsive G ene (BORG) as an enhancer of BCSC phenotypes. Indeed, we found BORG expression to: (i) correlate with stem cell markers Nanog, Aldh1a3, and Itga6 (α6 integrin/CD49f); (ii) enhance stem cell phenotypes in murine and human TNBC cells, and (iii) promote TNBC tumor initiation in mice. Mechanistically, BORG promoted BCSC phenotypes through its ability to interact physically with the E3 SUMO ligase TRIM28. Moreover, TRIM28 binding was observed in the promoter region of Itga6, whose genetic inactivation prevented BORG:TRIM28 complexes from: (i) inducing BCSC self-renewal and expansion in vitro, and (ii) eliciting BCSC metastatic outgrowth in the lungs of mice. Collectively, these findings implicate BORG:TRIM28 complexes as novel drivers of BCSC phenotypes in developing and progressing TNBCs. IMPLICATIONS: This work establishes the lncRNA BORG as a driver of BCSC phenotypes and the aggressive behaviors of TNBCs, events critically dependent upon the formation of BORG:TRIM28 complexes and expression of α6 integrin.

CPT1A and fatty acid ß-oxidation are essential for tumor cell growth and survival in hormone receptor-positive breast cancer.

Chromosome 11q13-14 amplification is a defining feature of high-risk hormone receptor-positive (HR+) breast cancer; however, the mechanism(s) by which this amplicon contributes to breast tumorigenesis remains unclear. In the current study, proteogenomic analyses of >3000 breast tumors from the TCGA, METABRIC and CPTAC studies demonstrated that carnitine palmitoyltransferase 1A (CPT1A), which is localized to this amplicon, is overexpressed at the mRNA and protein level in aggressive luminal tumors, strongly associated with indicators of tumor proliferation and a predictor of poor prognosis. In vitro genetic studies demonstrated that CPT1A is required for and can promote luminal breast cancer proliferation, survival, as well as colony and mammosphere formation. Since CPT1A is the rate-limiting enzyme during fatty acid oxidation (FAO), our data indicate that FAO may be essential for these tumors. Pharmacologic inhibition of FAO prevented in vitro and in vivo tumor growth and cell proliferation as well as promoted apoptosis in luminal breast cancer cells and orthotopic xenograft tumor models. Collectively, our data establish an oncogenic role for CPT1A and FAO in HR+ luminal tumors and provide preclinical evidence and rationale supporting further investigation of FAO as a potential therapeutic opportunity for the treatment of HR+ breast cancer.

Epigenetic plasticity in metastatic dormancy: mechanisms and therapeutic implications.

The overwhelming majority of cancer-associated morbidity and mortality can be ascribed to metastasis. Metastatic disease frequently presents in a delayed fashion following initial diagnosis and treatment, requiring that disseminated cancer cells (DCCs) spread early in tumor progression and persist in a dormant state at metastatic sites. To accomplish this feat, DCCs exhibit substantial phenotypic plasticity that is mediated by the epigenetic regulation of dormancy programs in response to intrinsic (i.e., cellular) and extrinsic (i.e., microenvironmental) cues. The epigenome is a dynamic landscape that encompasses transcriptional regulation via alteration of chromatin architecture, posttranscriptional RNA processing, and the diverse functions carried out by noncoding RNAs. Signals converging on DCCs are transduced through epigenetic effectors. Conversely, epigenetic regulation of gene expression controls the crosstalk between DCCs and cells of the metastatic niche, a phenomenon that is essential for the institution of dormant phenotypes. Importantly, epigenetic effectors can be targeted therapeutically, and the development of novel epigenetic therapies may provide new inroads to combating recurrent metastatic disease. Here we provide an overview of the dynamics of metastatic dormancy and summarize our current understanding of the intersections between dormancy and the epigenome, both mechanistically and therapeutically.

The IncRNA BORG: A novel inducer of TNBC metastasis, chemoresistance, and disease recurrence.

Although greater than 90% of breast cancer-related mortality can be attributed to metastases, the molecular mechanisms underpinning the dissemination of primary breast tumor cells and their ability to establish malignant lesions in distant tissues remain incompletely understood. Genomic and transcriptomic analyses identified a class of transcripts called long noncoding RNA (lncRNA), which interact both directly and indirectly with key components of gene regulatory networks to alter cell proliferation, invasion, and metastasis. We identified a pro-metastatic lncRNA BORG whose aberrant expression promotes metastatic relapse by reactivating proliferative programs in dormant disseminated tumor cells (DTCs). BORG expression is broadly and strongly induced by environmental and chemotherapeutic stresses, a transcriptional response that facilitates the survival of DTCs. Transcriptomic reprogramming in response to BORG resulted in robust signaling via survival and viability pathways, as well as decreased activation of cell death pathways. As such, BORG expression acts as a (i) marker capable of predicting which breast cancer patients are predisposed to develop secondary metastatic lesions, and (ii) unique therapeutic target to maximize chemosensitivity of DTCs. Here we review the molecular and cellular factors that contribute to the pathophysiological activities of BORG during its regulation of breast cancer metastasis, chemoresistance, and disease recurrence.

The role of functional, social, and mobility dynamics in facilitating older African Americans participation in clinical research.

PURPOSE: Older African Americans experience disproportionately higher incidence of morbidity and mortality related to chronic and infectious diseases, yet are significantly underrepresented in clinical research compared to other racial and ethnic groups. This study aimed to understand the extent to which social support, transportation access, and physical impediments function as barriers or facilitators to clinical trial recruitment of older African Americans. METHODS: Participants (N=221) were recruited from six African American churches in Atlanta and surveyed on various influences on clinical trial participation. RESULTS: Logistic regression models demonstrated that greater transportation mobility (odds ratio [OR]=2.10; p=0.007) and social ability (OR=1.77; p=0.02) were associated with increased intentions of joining a clinical trial, as was greater basic daily living ability (OR=3.25; p=0.03), though only among single participants. Among adults age ≥65 years, those with lower levels of support during personal crises were more likely to join clinical trials (OR=0.57; p=0.04). CONCLUSION: To facilitate clinical trial entry, recruitment efforts need to consider the physical limitations of their potential participants, particularly basic physical abilities and disabilities. Crisis support measures may be acting as a proxy for personal health issues among those aged >65 years, who would then be more likely to seek clinical trials for the personal health benefits. Outreach to assisted living homes, hospitals, and other communities is a promising avenue for improved clinical trial recruitment of older African Americans.

ENaC proteins are required for NGF-induced neurite growth.

Neurite growth is required for nervous system development and repair. Multiple signals, including neurotrophic factors and intact mechanosensing mechanisms, interact to regulate neurite growth. Degenerin/epithelial Na(+) channel (DEG/ENaC) proteins have been identified as putative mechanosensors in sensory neurons. Recently, others have shown that the neurotrophic factor NGF stimulates expression of acid-sensing ion channel molecules, which are members of the DEG/ENaC family. However, it is unknown whether NGF regulates ENaC expression or whether ENaC expression is required for neurite formation. Therefore, the aims of the present study were to determine whether ENaC expression is 1) regulated by NGF and 2) required for NGF-induced neurite growth in pheochromocytoma PC-12 cells. We found NGF-induced expression of beta- and gamma-subunits of ENaC, but not alpha-ENaC. Tyrosine kinase A (TrkA) receptor blockade abolished NGF-induced beta- and gamma-ENaC expression and neurite formation. NGF-induced neurite formation was inhibited by disruption of ENaC expression using 1) pharmacological blockade with benzamil, a specific ENaC inhibitor; 2) small interfering RNA; and 3) dominant-negative ENaC molecules. These data indicate NGF-TrkA regulation of ENaC expression may be required for neurite growth and may suggest a novel role for DEG/ENaC proteins in neuronal remodeling and differentiation.