Resf1 is a compound G4 quadruplex-associated tumor suppressor for triple negative breast cancer.

Patients with ER-negative breast cancer have the worst prognosis of all breast cancer subtypes, often experiencing rapid recurrence or progression to metastatic disease shortly after diagnosis. Given that metastasis is the primary cause of mortality in most solid tumors, understanding metastatic biology is crucial for effective intervention. Using a mouse systems genetics approach, we previously identified 12 genes associated with metastatic susceptibility. Here, we extend those studies to identify Resf1, a poorly characterized gene, as a novel metastasis susceptibility gene in ER- breast cancer. Resf1 is a large, unstructured protein with an evolutionarily conserved intron-exon structure, but with poor amino acid conservation. CRISPR or gene trap mouse models crossed to the Polyoma Middle-T antigen genetically engineered mouse model (MMTV-PyMT) demonstrated that reduction of Resf1 resulted in a significant increase in tumor growth, a shortened overall survival time, and increased incidence and number of lung metastases, consistent with patient data. Furthermore, an analysis of matched tail and primary tissues revealed loss of the wildtype copy in tumor tissue, consistent with Resf1 being a tumor suppressor. Mechanistic analysis revealed a potential role of Resf1 in transcriptional control through association with compound G4 quadruplexes in expressed sequences, particularly those associated with ribosomal biogenesis. These results suggest that loss of Resf1 enhances tumor progression in ER- breast cancer through multiple alterations in both transcriptional and translational control.

Aligning patient values and code status: Choice of Diction's Effect (CODE) study.

BACKGROUND: Decisions regarding resuscitation after cardiac arrest are critical from ethical, patient satisfaction, outcome, and healthcare cost standpoints. Physician-reported discussion barriers include topic discomfort, fear of time commitment, and difficulty articulating end-of-life concepts. The influence of language used in these discussions has not been tested. This study explored whether utilizing the alternate term "allow (a) natural death" changed code status decisions in hospitalized patients versus "do not resuscitate" (DNR). METHODS: All patients age 65 and over admitted to a general medicine hospital teaching service were screened (English-speaking, not ICU-level care, no active psychiatric illness, no substance misuse, no active DNR). Participants were randomized to resuscitation discussions with either DNR or "allow natural death" as the "no code" phrasing. Outcomes included patient resuscitation decision, satisfaction with and duration of the conversation, and decision correlation with illness severity and predicted resuscitation success. RESULTS: 102 participants were randomized to the "allow natural death" (N = 49) or DNR (N = 53) arms. The overall "no code" rate for our sample of hospitalized general medicine inpatients age >65 was 16.7%, with 13% in the DNR and 20.4% in the "allow natural death" arms (p = 0.35). Discussion length was similar in the DNR and "allow natural death" arms (3.9 + 3.2 vs. 4.9 + 3.9 minutes), and not significantly different (p = 0.53). Over 90% of participants were highly satisfied with their code status decision, without difference between arms (p = 0.49). CONCLUSIONS: Participants' code status discussions did not differ in "no code" rate between "allow natural death" and DNR arms but were short in length and had high patient satisfaction. Previously reported code status discussion barriers were not encountered. It is appropriate to screen code status in all hospitalized patients regardless of phrasing used.

SMARCD1 is a "Goldilocks" metastasis modifier.

Breast cancer is the most frequently diagnosed cancer worldwide, constituting around 15% of all diagnosed cancers in 2023. The predominant cause of breast cancer-related mortality is metastasis to distant essential organs, and a lack of metastasis-targeted therapies perpetuates dismal outcomes for late-stage patients. However, through our use of meiotic genetics to study inherited transcriptional network regulation, we have identified a new class of "Goldilocks" genes that are promising candidates for the development of metastasis-targeted therapeutics. Building upon previous work that implicated the CCR4-NOT RNA deadenylase complex in metastasis, we now demonstrate that the RNA-binding proteins (RNA-BPs) NANOS1, PUM2, and CPSF4 also regulate metastatic potential. Using cell lines, 3D culture, mouse models, and clinical data, we pinpoint Smarcd1 mRNA as a key target of all three RNA-BPs. Strikingly, both high and low expression of Smarcd1 is associated with positive clinical outcomes, while intermediate expression significantly reduces the probability of survival. Applying the theory of "essential genes" from evolution, we identify an additional 50 genes that span several cellular processes and must be maintained within a discrete window of expression for metastasis to occur. In the case of Smarcd1, small perturbations in its expression level significantly reduce metastasis in laboratory mouse models and alter splicing programs relevant to the ER+/HER2-enriched breast cancer subtype. The identification of subtype-specific "Goldilocks" metastasis modifier genes introduces a new class of genes and potential catalogue of novel targets that, when therapeutically "nudged" in either direction, may significantly improve late-stage patient outcomes.

"They're scared that somebody's gonna judge them": Female African American youth in foster care's perspectives on sexual and reproductive health communication with caregivers.

BACKGROUND: Obtaining accurate information is critical for youth's sexual and reproductive health (SRH). Youth not in foster care often learn about SRH from their biological parents. Separated from their biological parents, youth in care depend on healthcare providers and caregivers for SRH information. However, they often receive insufficient information and feel unsupported in meeting their needs for SRH information. PURPOSE: This study explored female African American adolescents in foster care's perspectives on effective SRH communication with caregivers to help them avoid sexual risks. METHODS: A qualitative study was conducted using semi-structured interviews. We used purposive sampling to recruit 16 adolescents aged 18 to 20 years old with a history of foster care placement. The transcribed interviews underwent inductive thematic analysis. The Positive Youth Development theory underpinned this research. RESULTS: Two prominent themes emerged: establishing a relationship and preferred communication approach. Youth reported that for caregivers to engage in effective SRH communication, they must first establish a relationship by being aware of the youth's childhood trauma, building trust, having patience, and being vulnerable. Youth also appreciated caregivers who ensured comfortability and were honest and straightforward. DISCUSSION: Caregivers should be trained on adverse childhood experiences, trauma-informed approaches, SRH knowledge, and communication. IMPLICATIONS TO PRACTICE: Healthcare providers should make use of the time spent with youth and discuss SRH topics during clinical encounters. This time spent with youth may be their only chance to obtain accurate SRH information. Youth's perspectives regarding communication about SRH should be implemented in future SRH communication interventions.

Provider Facilitation of Parent-Adolescent Health Communication: Findings From a National Survey.

INTRODUCTION: Primary care providers are well-positioned to facilitate parent-adolescent health communication. We examined provider-facilitated parent-adolescent health communication prevalence and associations with parent-adolescent health communication. METHOD: Using data from a national survey of parent-adolescent dyads (n = 853), we calculated the prevalence of provider-facilitated parent-adolescent health communication about 11 topics as a result of adolescent's last preventive visit. We examined correlates of of provider-facilitatedparent-adolescent communication and associations with with parent-adolescent communication. RESULTS: Eighteen percent of adolescents reported that a provider helped them talk with their parent about a health concern, with little variability by adolescent, parent, or provider characteristics. Prevalence of parent-adolescent communication because of an adolescent's last preventive visit ranged between 38.4% and 79.5%. Provider facilitation was positively associated with parent-adolescent communication for all topics. DISCUSSION: Given the low prevalence of provider-facilitated-parent-adolescent health communication and positive associations between provider facilitation and parent-adolescent communication about multiple important health-related topics, efforts to improve this practice could be beneficial.

Recent Advances in Understanding of Pathogenesis of Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) is one of the major diseases arising from chronic alcohol consumption and is one of the most common causes of liver-related morbidity and mortality. ALD includes asymptomatic liver steatosis, fibrosis, cirrhosis, and alcohol-associated hepatitis and its complications. The progression of ALD involves complex cell-cell and organ-organ interactions. We focus on the impact of alcohol on dysregulation of homeostatic mechanisms and regulation of injury and repair in the liver. In particular, we discuss recent advances in understanding the disruption of balance between programmed cell death and prosurvival pathways, such as autophagy and membrane trafficking, in the pathogenesis of ALD. We also summarize current understanding of innate immune responses, liver sinusoidal endothelial cell dysfunction and hepatic stellate cell activation, and gut-liver and adipose-liver cross talk in response to ethanol. In addition,we describe the current potential therapeutic targets and clinical trials aimed at alleviating hepatocyte injury, reducing inflammatory responses, and targeting gut microbiota, for the treatment of ALD.

Role of the chemokine system in liver fibrosis: a narrative review.

Background and Objective: Liver fibrosis is a disease with characteristics of an aberrant wound healing response. Fibrosis is commonly the end-stage for chronic liver diseases like alcohol-associated liver disease (ALD), metabolic-associated liver disease, viral hepatitis, and hepatic autoimmune disease. Innate immunity contributes to the progression of many diseases through multiple mechanisms including production of pro-inflammatory mediators, leukocyte infiltration and tissue injury. Chemokines and their receptors orchestrate accumulation and activation of immune cells in tissues and are associated with multiple liver diseases; however, much less is known about their potential roles in liver fibrosis. This is a narrative review of current knowledge of the relationship of chemokine biology to liver fibrosis with insights into potential future therapeutic opportunities that can be explored in the future. Methods: A comprehensive literature review was performed searching PubMed for relevant English studies and texts regarding chemokine biology, chronic liver disease and liver fibrosis published between 1993 and 2021. The review was written and constructed to detail the intriguing chemokine biology, the relation of chemokines to tissue injury and resolution, and identify areas of discovery for fibrosis treatment. Key Content and Findings: Chemokines are implicated in many chronic liver diseases, regardless of etiology. Most of these diseases will progress to fibrosis without appropriate treatment. The contributions of chemokines to liver disease and fibrosis are diverse and include canonical roles of modulating hepatic inflammation as well as directly contributing to fibrosis via activation of hepatic stellate cells (HSCs). Limited clinical evidence suggests that targeting chemokines in certain liver diseases might provide a therapeutic benefit to patients with hepatic fibrosis. Conclusions: The chemokine system of ligands and receptors is a complex network of inflammatory signals in nearly all diseases. The specific sources of chemokines and cellular targets lend unique pathophysiological consequences to chronic liver diseases and established fibrosis. Although most chemokines are pro-inflammatory and contribute to tissue injury, others likely aid in the resolution of established fibrosis. To date, very few targeted therapies exist for the chemokine system and liver disease and/or fibrosis, and further study could identify viable treatment options to improve outcomes in patients with end-stage liver disease.

Pulsed Electromagnetic Field Therapy for Pain Management in Interstitial Cystitis/Bladder Pain Syndrome: A Proof-of-Concept Case Series.

OBJECTIVE: To evaluate the efficacy of pulsed electromagnetic field (PEMF) therapy for symptom and pain management in women with non-bladder centric interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: Women with non-bladder centric IC/BPS and a numeric rating scale score for pelvic pain ≥6 underwent twice-daily 8-minute full body PEMF therapy sessions for 4 weeks. The primary outcome metric was a reduction in pelvic pain score ≥2 points. A 7-day voiding diary (collected at baseline and conclusion), 3 validated symptom scores, and the Short Form-36 Quality of Life questionnaire (completed at baseline, conclusion of treatment, and 8-week follow-up), were used to assess secondary outcomes. Treatment effects were analyzed via Wilcoxon-signed rank test; P < .05 was considered significant. RESULTS: The 4-week treatment protocol was completed by 8 of 10 enrolled patients, and 7:8 (87.5%) had a significant reduction in pelvic pain (-3.0 points, P = .011) after 4 weeks. There was also a significant decrease in scores on all validated IC/BPS questionnaires, daily number of voids, and nocturia symptom score (P < .05). Significant increases in several quality-of-life questionnaire sub-scores were also identified at 4 weeks (P < .05). At 8-week post-therapy, the positive effects were somewhat attenuated, yet 4:8 patients (50%) continued to have significant pain reduction (P = .047). No adverse events or side effects were reported. CONCLUSION: Whole body pulsed electromagnetic field therapy is an alternative treatment option for women with chronic bladder pain syndrome that warrants investigation through comparative trials.

Parents' Sources of Adolescent Sexual Health Information and Their Interest in Resources From Primary Care.

OBJECTIVE: To examine sources of information used by parents to facilitate parent-adolescent communication about sexual and reproductive health (SRH), parents' preferences for receiving SRH information through primary care, and factors associated with parents' interest in primary-care-based SRH information (ie, resources recommended or offered in the primary care setting). METHODS: In this cross-sectional study, a nationally representative sample of 11-17-year-old adolescents and their parents (n = 1005 dyads) were surveyed online; 993 were retained for these analyses. Parents were asked about their use of 11 resources to help them talk with their adolescents about SRH and rated the likelihood of using specific primary-care-based resources. We used multivariable logistic regression to examine characteristics associated with parent interest in primary-care-based SRH resources. RESULTS: Only 25.8% of parents reported receiving at least a moderate amount of SRH information from primary care; half (53.3%) reported receiving no SRH information from their adolescent's provider. Parents received the most information from personal connections (eg, spouse/partner, friends). Most parents (59.1%) reported being likely to utilize a primary-care-based resource for SRH information. Parents who previously received SRH information from primary care sources had greater odds of reporting they would be likely to utilize a primary-care-based resources (AOR = 4.06, 95% CI: 2.55-6.46). CONCLUSIONS: This study provides insights into parents' sources of information for communicating with their adolescents about SRH and ways primary care practices might increase support for parents in having SRH conversations with their adolescents. Future studies are needed to establish clinical best practices for promoting parent-adolescent communication about SRH.

Pulsed electromagnetic field (PEMF) as an adjunct therapy for pain management in interstitial cystitis/bladder pain syndrome.

INTRODUCTION AND HYPOTHESIS: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often experience chronic pelvic and even systemic pain that can be difficult to clinically manage. Pulsed electromagnetic field (PEMF) therapy, a non-invasive strategy that has shown significant efficacy for pain reduction in other chronic pain conditions, may provide benefit for pain management in patients with IC/BPS. METHODS: PEMF delivery to patients occurs via a bio-electromagnetic-energy device which consists of a flexible mat (180 × 50 cm) that the patient lies on for systemic, full-body delivery and/or a flexible pad (50 × 15 cm) for targeted delivery to a specific body region (e.g., pelvic area). The duration of individual sessions, number of sessions per day, total number of sessions, and follow-up observation period vary between previously published studies. Positive outcomes are typically reported as a significant reduction in visual analog scale (VAS) pain score and functional improvement assessed using validated questionnaires specific to the condition under study. RESULTS AND CONCLUSIONS: The use of PEMF has been evaluated as a therapeutic strategy for pain management in several clinical scenarios. Randomized, double-blinded, placebo-controlled trials have reported positive efficacy and safety profiles when PEMF was used to treat non-specific low back pain, patellofemoral pain syndrome, chronic post-operative pain, osteoarthritis-related pain, rheumatoid arthritis-related pain, and fibromyalgia-related pain. Based on these positive outcomes in a variety of pain conditions, clinical trials to evaluate whether PEMF can provide a safe, non-invasive therapeutic approach to improve symptoms of chronic pain and fatigue in patients with IC/BPS are warranted.

South African university women's perspectives on intimate partner violence: a qualitative study of reactions to a tailored vignette.

Intimate partner violence is an ongoing issue in South Africa, which has the highest rates of violence against women and girls in the world. Intimate partner violence is common in Limpopo, where women, including university students, experience elevated rates of violent crime. This qualitative study was conducted to examine university students' perspectives regarding intimate partner violence among their peers. A culturally tailored vignette was used to prompt reflection from 38 female university students in Limpopo. Audiotaped responses to the vignette were transcribed, coded and analysed using thematic analysis. Four main themes were developed from participants' responses to the vignette: cultural beliefs, the university's role in intimate partner violence, likely outcomes of intimate partner violence, and future interventions. Intimate partner violence was seen as a common problem within the university. Students' responses indicated that cultural beliefs perpetuated violence against women, with women entering and remaining in abusive relationships for financial security or resources such as housing. Students also reported lack of adequate on-campus housing options, limited knowledge of intimate partner violence, and few actions to reduce intimate partner violence, all of which placed then at heightened risk of intimate partner violence.

Differential role of MLKL in alcohol-associated and non-alcohol-associated fatty liver diseases in mice and humans.

Hepatocellular death contributes to progression of alcohol-associated (ALD-associated) and non-alcohol-associated (NAFL/NASH) liver diseases. However, receptor-interaction protein kinase 3 (RIP3), an intermediate in necroptotic cell death, contributes to injury in murine models of ALD but not NAFL/NASH. We show here that a differential role for mixed-lineage kinase domain-like protein (MLKL), the downstream effector of RIP3, in murine models of ALD versus NAFL/NASH and that RIP1-RIP3-MLKL can be used as biomarkers to distinguish alcohol-associated hepatitis (AH) from NASH. Phospho-MLKL was higher in livers of patients with NASH compared with AH or healthy controls (HCs). MLKL expression, phosphorylation, oligomerization, and translocation to plasma membrane were induced in WT mice fed diets high in fat, fructose, and cholesterol but not in response to Gao-binge (acute on chronic) ethanol exposure. Mlkl-/- mice were not protected from ethanol-induced hepatocellular injury, which was associated with increased expression of chemokines and neutrophil recruitment. Circulating concentrations of RIP1 and RIP3, but not MLKL, distinguished patients with AH from HCs or patients with NASH. Taken together, these data indicate that MLKL is differentially activated in ALD/AH compared with NAFL/NASH in both murine models and patients. Furthermore, plasma RIP1 and RIP3 may be promising biomarkers for distinguishing AH and NASH.

In Vivo Evidence for Serine Biosynthesis-Defined Sensitivity of Lung Metastasis, but Not of Primary Breast Tumors, to mTORC1 Inhibition.

In tumors, nutrient availability and metabolism are known to be important modulators of growth signaling. However, it remains elusive whether cancer cells that are growing out in the metastatic niche rely on the same nutrients and metabolic pathways to activate growth signaling as cancer cells within the primary tumor. We discovered that breast-cancer-derived lung metastases, but not the corresponding primary breast tumors, use the serine biosynthesis pathway to support mTORC1 growth signaling. Mechanistically, pyruvate uptake through Mct2 supported mTORC1 signaling by fueling serine biosynthesis-derived α-ketoglutarate production in breast-cancer-derived lung metastases. Consequently, expression of the serine biosynthesis enzyme PHGDH was required for sensitivity to the mTORC1 inhibitor rapamycin in breast-cancer-derived lung tumors, but not in primary breast tumors. In summary, we provide in vivo evidence that the metabolic and nutrient requirements to activate growth signaling differ between the lung metastatic niche and the primary breast cancer site.

"I'm not Gonna Die Because of an STD": Female African American Adolescents' Perspectives on how they Protected Themselves from Sexual Risks While in Foster Care.

PURPOSE: Youth in foster care are at greater risk for engaging in sexual behaviors that increase their odds of experiencing negative sexual and reproductive health (SRH) outcomes. The purpose of this qualitative study was to describe challenges faced by female African American adolescents in foster care as they tried to protect themselves from SRH risks and protective beliefs and behaviors to avoid these risks. DESIGN AND METHODS: Semi-structured interviews were conducted with 16 female African American adolescents, ages 18-20 years, with a history of foster care placement during adolescence. Purposive sampling was done to recruit participants from a metropolitan area in Virginia. Transcribed interviews underwent inductive thematic analysis. This paper focuses on the theme of protection from SRH risks and its subthemes of challenges that made it difficult to avoid sexual risks and protective beliefs and behaviors that facilitated avoidance of those risks. RESULTS: Participants reported yearning for connection, partners' desire to not use condoms, and judgmental caregivers as challenges. Protective beliefs and behaviors included open communication with their caregivers about SRH, abstinence, contraceptive use, and participants' desire to be healthy. CONCLUSIONS: Study findings shed light on protective beliefs and behaviors female youth in foster care used to safeguard themselves from negative SRH outcomes. Youth at times lacked agency in sexual decision-making and contraceptive use. PRACTICE IMPLICATIONS: Findings highlight the importance of sexual relationships and partner communication related to contraceptive use, and offering trauma-informed interventions, including culturally sensitive counseling regarding long acting reversible contraception.

Tumor volume reduction evaluated by cone beam computed tomography during stereotactic body radiotherapy for early stage non-small cell lung cancer.

BACKGROUND: We hypothesized that significant tumor volume reduction (TVR) occurs over the course of stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer (NSCLC), and that TVR correlates with clinical outcomes. METHODS: We conducted a retrospective review of patients treated with SBRT for early stage NSCLC across two academic centers. For each patient, we contoured the tumor volume (TV) on cone beam computed tomography (CBCT) images obtained before each treatment fraction. We then calculated TVR based on the TV from the first and last days of treatment. We used log-rank tests to quantify differences in overall survival (OS), progression-free survival (PFS) and recurrence based on TVR. RESULTS: Data from 69 patients and a total of 73 treated tumors were analyzed. The median follow-up for survivors was 51.8 months (range, 6.9 to 80.0 months). The median TVR for the cohort was 10.1% (range, -5.7% to 43.5%). There was no significant difference in either OS (median 33.4 vs. 29.1 months, P=0.79) or PFS (median 26.3 vs. 12.3 months, P=0.43) for those with high TVRs (≥10.1%) vs. low TVRs (<10.1%), respectively. There was a trend toward superior 2-year PFS in the high TVR group (52.2% vs. 36.7%, P=0.062), but this effect diminished on longer follow-up (4-year PFS 31.9% vs. 26.7%, P=0.15). No associations were observed between TVR and local, regional or distant recurrence. CONCLUSIONS: We were not able to demonstrate that TVR is a reliable predictive imaging marker for stage I/II NSCLC treated with SBRT. Future studies with larger sample sizes are needed to clarify a potential relationship between TVR and early outcomes.

Metastasis-Specific Gene Expression in Autochthonous and Allograft Mouse Mammary Tumor Models: Stratification and Identification of Targetable Signatures.

Breast cancer metastasis is a leading cause of cancer-related death of women in the United States. A hurdle in advancing metastasis-targeted intervention is the phenotypic heterogeneity between primary and secondary lesions. To identify metastasis-specific gene expression profiles we performed RNA-sequencing of breast cancer mouse models; analyzing metastases from models of various drivers and routes. We contrasted the models and identified common, targetable signatures. Allograft models exhibited more mesenchymal-like gene expression than genetically engineered mouse models (GEMM), and primary culturing of GEMM-derived metastatic tissue induced mesenchymal-like gene expression. In addition, metastasis-specific transcriptomes differed between tail vein and orthotopic injection of the same cell line. Gene expression common to models of spontaneous metastasis included sildenafil response and nicotine degradation pathways. Strikingly, in vivo sildenafil treatment significantly reduced metastasis by 54%, while nicotine significantly increased metastasis by 46%. These data suggest that (i) actionable metastasis-specific pathways can be readily identified, (ii) already available drugs may have great potential to alleviate metastatic incidence, and (iii) metastasis may be influenced greatly by lifestyle choices such as the choice to consume nicotine products. In summary, while mouse models of breast cancer metastasis vary in ways that must not be ignored, there are shared features that can be identified and potentially targeted therapeutically. IMPLICATIONS: The data we present here exposes critical variances between preclinical models of metastatic breast cancer and identifies targetable pathways integral to metastatic spread. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/9/1278/F1.large.jpg.

Crop Resilience to Drought With and Without Response Diversity.

In the face of increasingly frequent droughts threatening crop performance, ecological theory suggests that higher species diversity may help buffering productivity by making systems more resistant through resource complementarity and more resilient through higher response diversity. However, empirical evidence for these diversity effects under drought stress has remained patchy. In two pot experiments, we explored whether mixing two legume species with a contrasting response to water availability, alsike clover (AC) and black medic (BM), promotes resistance to cumulative drought stress, and resilience of aboveground crop biomass to a transient drought event. The mixture was more productive than the average of the sole crops, and this mixture effect was higher in the non-stressed than in the drought-stressed plants. However, with six levels of constant drought intensities, the mixture effect was not consistently affected by drought level. Response diversity was evident as asynchrony of growth in the two species after the drought event, with BM re-growing faster than AC. Significant resilience to drought was observed in sole AC, i.e., without response diversity. Resilience was larger in AC than in BM and increased from 44 to 72 days after sowing (DAS). The mixture was more resilient than the average resilience of the sole crops at 72 DAS, but it was never more resilient than AC, indicating that resilience is promoted by, but not dependent on response diversity. We conclude that crop diversity may contribute to drought resilience through growth asynchrony, but that species identity plays a crucial role in making systems more drought-resilient.

The genomic landscape of metastasis in treatment-naïve breast cancer models.

Metastasis remains the principle cause of mortality for breast cancer and presents a critical challenge because secondary lesions are often refractory to conventional treatments. While specific genetic alterations are tightly linked to primary tumor development and progression, the role of genetic alteration in the metastatic process is not well-understood. The theory of tumor evolution postulated by Peter Nowell in 1976 has yet to be proven in the context of metastasis. Therefore, in order to investigate how somatic evolution contributes to breast cancer metastasis, we performed exome, whole genome, and RNA sequencing of matched metastatic and primary tumors from pre-clinical mouse models of breast cancer. Here we show that in a treatment-naïve setting, recurrent single nucleotide variants and copy number variation, but not gene fusion events, play key metastasis-driving roles in breast cancer. For instance, we identified recurrent mutations in Kras, a known driver of colorectal and lung tumorigenesis that has not been previously implicated in breast cancer metastasis. However, in a set of in vivo proof-of-concept experiments we show that the Kras G12D mutation is sufficient to significantly promote metastasis using three syngeneic allograft models. The work herein confirms the existence of metastasis-driving mutations and presents a novel framework to identify actionable metastasis-targeted therapies.

Integrated analyses of murine breast cancer models reveal critical parallels with human disease.

Mouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. Here, we complete whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. Through integrative in vitro and in vivo studies, we identify copy number alterations in key extracellular matrix proteins including collagen 1 type 1 alpha 1 (COL1A1) and chondroadherin (CHAD) that drive metastasis in these mouse models. In addition to copy number alterations, we observe a propensity of the tumors to modulate tyrosine kinase-mediated signaling through mutation of phosphatases such as PTPRH in the MMTV-PyMT mouse model. Mutation in PTPRH leads to increased phospho-EGFR levels and decreased latency. These findings underscore the importance of understanding the complete genomic landscape of a mouse model and illustrate the utility this has in understanding human cancers.