BIPOC experiences of (anti-)racist patient engagement in adolescent and young adult oncology research: an electronic Delphi study.

Aims: To characterize Black, Indigenous and People of Color (BIPOC) adolescent and young adult (AYA) cancer patients' experiences of patient engagement in AYA oncology and derive best practices that are co-developed by BIPOC AYAs and oncology professionals. Materials & methods: Following a previous call to action from AYA oncology professionals, a panel of experts composed exclusively of BIPOC AYA cancer patients (n = 32) participated in an electronic Delphi study. Results: Emergent themes described BIPOC AYA cancer patients' direct experiences and consensus opinion on recommendations to advance antiracist patient engagement from BIPOC AYA cancer patients and oncology professionals. Conclusion: The findings reveal high-priority practices across all phases of research and are instructional for advancing health equity.

Can everyone hear me? Reflections on the use of global online workshops for promoting inclusive knowledge generation.

Online research methods have risen in popularity over recent decades, particularly in the wake of COVID-19. We conducted five online workshops capturing the experiences of participatory health researchers in relation to power, as part of a collaborative project to develop global knowledge systems on power in participatory health research. These workshops included predominantly academic researchers working in 24 countries across Africa, Asia, Europe, and the Americas. Here, we reflect on the opportunities, limitations, and key considerations of using online workshops for knowledge generation and shared learning. The online workshop approach offers the potential for cross-continental knowledge exchange and for the amplification of global South voices. However, this study highlights the need for deeper exploration of power dynamics exposed by online platform use, particularly the 'digital divide' between academic partners and community co-researchers. Further research is needed to better understand the role of online platforms in generating more inclusive knowledge systems.

Planning for Community Scale-Up of Project HEAL: Insights From the SPRINT Initiative.

Project HEAL (Health through Early Awareness and Learning) is an evidence-based intervention rooted in health behavior change theory and aims to increase cancer awareness and early detection through African American faith-based organizations. This study explored the potential for broader scale-up and dissemination of Project HEAL with the team's participation in a training program called Speeding Research-Tested INTerventions (SPRINT). The SPRINT training was framed using tools from the Business Model Canvas and the Value Proposition Canvas to guide trainees in designing (1) compelling value propositions, (2) a minimal viable product, and (3) questions to gain critical insight from various stakeholders during a process called Customer Discovery. We report on our experiences and insights on intervention scale-up that we gained from the training, including key findings from 41 discovery interviews conducted with various stakeholders of the church. We learned several valuable lessons from the discovery interviews such as scale-up will likely be more incremental than immediate. Additional refinement is needed to scale up the intervention for "real-world" application, such as making our technology more user-friendly and including additional health topics beyond cancer. We discuss how insights from the training refined our plans for future scale-up and dissemination in a constituent-informed way.

Mechanisms of immune evasion in breast cancer.

Tumors develop multiple mechanisms of immune evasion as they progress, with some cancer types being inherently better at 'hiding' than others. With an increased understanding of tumor immune surveillance, immunotherapy has emerged as a promising treatment strategy for breast cancer, despite historically being thought of as an immunologically silent neoplasm. Some types of cancer, such as melanoma, bladder, and renal cell carcinoma, have demonstrated a durable response to immunotherapeutic intervention, however, breast neoplasms have not shown the same efficacy. The causes of breast cancer's immune silence derive from mechanisms that diminish immune recognition and others that promote strong immunosuppression. It is the mechanisms of immune evasion in breast cancers that are poorly defined. Thus, further characterization is critical for the development of better therapies. This brief review will seek to provide insight into the possible causes of weak immunogenicity and immune suppression mediated by breast cancers and highlight current immunotherapies being used to restore immune responses to breast cancer.

A pilot study of FDG PET/CT detects a link between brown adipose tissue and breast cancer.

BACKGROUND: Breast cancer is the second most lethal cancer in women. Understanding biological mechanisms that cause progression of this disease could yield new targets for prevention and treatment. Recent experimental studies suggest that brown adipose tissue (BAT) may play a key role in breast cancer progression. The primary objective for this pilot study was to determine if the prevalence of active BAT in patients with breast cancer is increased compared to cancer patients with other malignancies. METHODS: We retrospectively analyzed data from 96 breast cancer patients who had FDG PET/CT scan for routine staging at the University of Maryland and 96 age- and weight-matched control female patients with other malignancies (predominantly colon cancer) who had undergone FDG PET/CT imaging on the same day. Data on the distribution (bilateral upper neck, supraclavicular and paraspinal regions) and intensity (SUVmax) of active BAT were evaluated by 2 Nuclear Medicine physicians, blinded to the clinical history. RESULTS: We found sufficient evidence to conclude that based on our sample data the prevalence of active BAT in breast cancer patients' group is significantly different from that in the control group. The estimated frequency of BAT activity was 3 fold higher in breast cancer patients as compared to controls with other cancers, (16.7% vs. 5.2%, respectively, p = 0.019). When patients were stratified by age in order to determine the possible impact of age related hormonal changes on active BAT among the younger women (≤ 55 years of age), 25.6% breast cancer patients exhibited BAT activity compared to only 2.8% in control women (p = 0.007). In contrast, among the older women (> 55 years of age), the prevalence of active BAT was similar among breast cancer and control women (10.7% vs 6.7%). CONCLUSIONS: In breast cancer patients prevalence of BAT activity on FDGPET/CT is 3-fold greater than in age- and body weight-matched patients with other solid tumor malignancies; this difference is particularly striking among younger women aged < =55. In summary, our retrospective clinical data provide support to pursue prospective clinical and translational studies to further define the role of BAT in breast cancer development and progression.

Exploring power and power sharing in participatory health research partnerships: A scoping review protocol.

INTRODUCTION: Participatory health research (PHR) as a research paradigm, guides the research process and strives to achieve positive change in society in the interest of people's health. In this scoping review, PHR will be used as an umbrella term considering a wide range of collaborative research approaches in the health context. PHR is conducted 'with' or 'by' those it intends to benefit, as opposed to 'on' and 'for' them. Their involvement throughout the research process seeks to shift power and decision-making from where they traditionally lay within academia toward community, patient and public end-users. Research cannot be truly participatory without concurrently addressing power dynamics within the partnership and power imbalances in decision making. Therefore, power sharing can be defined as a major factor in building effective academic-community collaborations. This scoping review aims to identify, clarify, and map existing literature on power and power sharing in PHR from both theoretical and practical perspectives. Specifically, we will explore how power is conceptualised throughout the literature, and how power and power sharing are applied and addressed in real-life PHR partnerships. MATERIALS AND METHODS: This scoping review will be conducted in accordance with the guidelines outlined in the Joanna Briggs Institute (JBI) Reviewer's Manual. This scoping review will consider both empirical and non-empirical research that report on understanding power and power sharing in participatory health research partnerships. All appropriate studies will be retrieved from the following five electronic databases: PubMed, Scopus, Embase, PsycINFO, SocIndex. This review will be limited to articles published in English and from January 1998 to March 2024. As the scoping review aims to capture more than peer-reviewed and published literature, it will also include grey literature such as theses and dissertations, reports, conference proceedings, and editorials. Data from the included literature will be extracted based on the data extraction tool, defined in advance. ETHICS AND DISSEMINATION: As primary data will not be collected, ethical approval is not required to conduct the scoping review. The findings of this study will be disseminated through peer-reviewed publications.

Prevalence, trends, and factors associated with maternal autonomy regarding healthcare, finances, and mobility in Bangladesh: Analysis of Demographic and Health Surveys 1999-2018.

Maternal autonomy is associated with improved healthcare utilization/outcomes for mothers and babies in low- and middle-income countries. We investigated the trends in the prevalence and factors associated with maternal autonomy in Bangladesh. This cross-sectional study analyzed the Bangladesh Demographic and Health Survey for 1999-00, 2004, 2007, 2011, 2014, and 2017-18. Maternal autonomy was defined as at least one decision-making ability regarding healthcare, large household purchases, and freedom of mobility. We included 15-49-year-old mothers with at least one live-birth in the past three years. We compared the samples based on the presence of autonomy and reported the trends in prevalence (95% confidence intervals (CIs)) across the survey years. Lastly, we performed multilevel logistic regression to report prevalence odds ratios (PORs) for the associated factors. Variables investigated as potential factors included maternal age, number of children, maternal education, paternal education, current work, religion, mass media exposure, wealth quintile, place and division of residence, and survey years. The prevalence of 'any' maternal autonomy was 72.0% (95% CI: 70.5-73.5) in 1999-00 and increased to 83.8% (95% CI: 82.7-84.9) in 2017-18. In adjusted analysis, mothers with older age, higher education, work outside the home, and mass media exposure had higher odds of autonomy than their counterparts (POR > 1, p < 0.05). For instance, compared to mothers without any formal education, the odds of autonomy were significantly (p < 0.001) higher among mothers with primary (adjusted POR: 1.2, 95% CI: 1.1-1.4), secondary (adjusted POR: 1.4, 95% CI: 1.2-1.6), and college/above (adjusted POR: 1.9, 95% CI: 1.6-2.2) education. While the level of maternal autonomy has increased, a substantial proportion still do not have autonomy. Expanding educational and earning opportunities may increase maternal autonomy. Further research should investigate other ways to improve it as well.

Perspectives on Benefits and Challenges to Developing a Co-Teaching and Co-Learning Exchange between Community and Academic Partners.

BACKGROUND: To train future professionals in health disparities and social determinants of health, academic health centers often use curricula exclusively developed and instructed by faculty. OBJECTIVE: To examine the perceptions and attitudes of faculty and community stakeholders towards the benefits of and challenges to developing co-teaching/co-learning exchange programs. METHODS: Faculty from six academic professional schools at a single institution and community members participated in focus groups. Interviews were video-recorded and reviewed for themes. RESULTS: Both faculty and community participants felt that partnering in the design and implementation of lectures addressing the social determinants of health could enhance curriculum and provide real-world context for the learning experience. CONCLUSIONS: Our findings add to the literature examining the benefits and challenges of engagement between faculty and community and offer new insights on the value of co-teaching/co-learning experiences.

A Student-Centered, Entrepreneurship Development (ASCEND) Undergraduate Summer Research Program: Foundational Training for Health Research.

Increasing the participation of students of African descent and other minoritized populations in the scientific workforce is imperative in generating a more equitable biomedical research infrastructure and increasing national research creativity and productivity. Undergraduate research training programs have shown to be essential tools in retaining underrepresented minority (URM) students in the sciences and attracting them into STEM and biomedical careers. This paper describes an innovative approach to harness students' entrepreneurial desire for autonomy and creativity in a Summer Research Institute (SRI) that has served as an entry point into a multiyear, National Institutes of Health Building Infrastructure Leading to Diversity (NIH BUILD)-funded research training program. The SRI was designed as an 8-week, student-centered and course-based research model in which students select their own research topics. We test here the effects of SRI training on students' science self-efficacy and science identity, along with several other constructs often associated with academic outcomes in the sciences. The data shown here comprise analysis of four different training cohorts throughout four subsequent summers. We show significant gains in students' science self-efficacy and science identity at the conclusion of SRI training, as well as academic adjustment and sense of belonging. SRI participants also displayed substantially improved retention in their science majors and graduation rates.

Anticipatory Guidance: Developing a Patient Navigation Pathway to Reduce the Financial Toxicity of Cancer.

Background: Healthcare providers have an influential role in the experience of financial toxicity among their cancer patients, yet patients commonly report unmet needs and dissatisfaction regarding communication with their providers about financial concerns. Aims: The purpose of this study is to develop a novel financial navigation pathway that leverages existing patient financial services and resources with corresponding patient-centered, community-informed strategies, via study participants, that may be utilized in routine care to reduce financial hardship among cancer patients. Methods: We conducted in-depth interviews (n=50) with 34 cancer patients and 16 cancer care professionals at a National Cancer Institute designated comprehensive cancer center located in a dense urban area of the US between December2022 to June 2023. Results: Content analyses resulted in emergent themes and representative quotations on experiences of financial hardship within the material, behavioral, and psychosocial domains. Investigators used emergent themes to develop financial strategies and construct a financial navigation pathway to screen patients for and intervene upon the financial toxicity of cancer in routine care. Conclusion: This study followed an innovative approach by constructing a financial navigation pathway tool that follows the oncological workflow at a National Cancer Institute designated comprehensive cancer center. Future research is needed to test the tool's impact on financial toxicity, cancer outcomes, and other health-related outcomes, and to better understand how much patient navigation is needed to bring about meaningful change.

Comparison of radioimmuno and carbon nanotube field-effect transistor assays for measuring insulin-like growth factor-1 in a preclinical model of human breast cancer.

BACKGROUND: To realize the promise of personalized medicine, diagnostic instruments used for detecting and measuring biomarkers must become smaller, faster and less expensive. Although most techniques used currently to detect biomarkers are sensitive and specific, many suffer from several disadvantages including their complexity, high cost and long turnaround time. One strategy to overcome these problems is to exploit carbon nanotube (CNT) based biosensors, which are sensitive, use inexpensive disposable components and can be easily adapted to current assay protocols. In this study we investigated the applicability of using a CNT field-effect transistor (CNT-FET) as a diagnostic instrument for measuring cancer biomarkers in serum using a mouse model of Breast Cancer Susceptibility 1-related breast cancer. Insulin like growth factor-1 (IGF-1) was chosen because it is highly relevant in breast cancer and because measuring serum IGF-1 levels by conventional methods is complicated due to specific IGF-1 serum binding proteins. FINDINGS: Our results show that there is good correlation between the two platforms with respect to detecting serum IGF-1. In fact, the CNT-FETs required only one antibody, gave real-time results and required approximately 100-fold less mouse serum than the radioimmunoassay. CONCLUSIONS: Both IGF-1 radioimmuno and CNT-FET assays gave comparable results. Indeed, the CNT-FET assay was simpler and faster than the radioimmunoassay. Additionally, the low serum sample required by CNT-FETs can be especially advantageous for studies constricted by limited amount of human clinical samples and for mouse studies, since animals often need to be sacrificed to obtain enough serum for biomarker evaluation.

Inbred Strain Characteristics Impact the NKT Cell Repertoire.

NKT cells are primed lymphocytes that rapidly secrete cytokines and can directly kill cancerous cells. Given the critical role NKT cells play in cancer immune surveillance, we sought to investigate the effect of mutations in Brca1, specifically a conditional deletion of exon 11, on type I invariant NKT cell development. We observed a significant reduction in invariant NKT cells in both primary lymphoid and peripheral organs in Brca1 mutant mice compared with wild-type C57BL/6. However, the original Brca1 mutant strain was on a mixed background containing FVB/N. We determined that strain differences, rather than mutations in Brca1, led to the observed loss in NKT cells. Importantly, we found that whereas FVB/N mice lack Vß8, there was a striking increase in the total number of thymic type I CD1d-α-galactosylceramide tetramer positive NKT cells and skewing of the NKT cell population to NKT2 compared with C57BL/6 mice. Collectively, our data demonstrate the profound effect genetics can have on NKT cell subset differentiation.

'You want to deal with power while riding on power': global perspectives on power in participatory health research and co-production approaches.

INTRODUCTION: Power relations permeate research partnerships and compromise the ability of participatory research approaches to bring about transformational and sustainable change. This study aimed to explore how participatory health researchers engaged in co-production research perceive and experience 'power', and how it is discussed and addressed within the context of research partnerships. METHODS: Five online workshops were carried out with participatory health researchers working in different global contexts. Transcripts of the workshops were analysed thematically against the 'Social Ecology of Power' framework and mapped at the micro (individual), meso (interpersonal) or macro (structural) level. RESULTS: A total of 59 participants, with participatory experience in 24 different countries, attended the workshops. At the micro level, key findings included the rarity of explicit discussions on the meaning and impact of power, the use of reflexivity for examining assumptions and power differentials, and the perceived importance of strengthening co-researcher capacity to shift power. At the meso level, participants emphasised the need to manage co-researcher expectations, create spaces for trusted dialogue, and consider the potential risks faced by empowered community partners. Participants were divided over whether gatekeeper engagement aided the research process or acted to exclude marginalised groups from participating. At the macro level, colonial and 'traditional' research legacies were acknowledged to have generated and maintained power inequities within research partnerships. CONCLUSIONS: The 'Social Ecology of Power' framework is a useful tool for engaging with power inequities that cut across the social ecology, highlighting how they can operate at the micro, meso and macro level. This study reiterates that power is pervasive, and that while many researchers are intentional about engaging with power, actions and available tools must be used more systematically to identify and address power imbalances in participatory research partnerships, in order to contribute to improved equity and social justice outcomes.

Comparison of mouse mammary gland imaging techniques and applications: reflectance confocal microscopy, GFP imaging, and ultrasound.

BACKGROUND: Genetically engineered mouse models of mammary gland cancer enable the in vivo study of molecular mechanisms and signaling during development and cancer pathophysiology. However, traditional whole mount and histological imaging modalities are only applicable to non-viable tissue. METHODS: We evaluated three techniques that can be quickly applied to living tissue for imaging normal and cancerous mammary gland: reflectance confocal microscopy, green fluorescent protein imaging, and ultrasound imaging. RESULTS: In the current study, reflectance confocal imaging offered the highest resolution and was used to optically section mammary ductal structures in the whole mammary gland. Glands remained viable in mammary gland whole organ culture when 1% acetic acid was used as a contrast agent. Our application of using green fluorescent protein expressing transgenic mice in our study allowed for whole mammary gland ductal structures imaging and enabled straightforward serial imaging of mammary gland ducts in whole organ culture to visualize the growth and differentiation process. Ultrasound imaging showed the lowest resolution. However, ultrasound was able to detect mammary preneoplastic lesions 0.2 mm in size and was used to follow cancer growth with serial imaging in living mice. CONCLUSION: In conclusion, each technique enabled serial imaging of living mammary tissue and visualization of growth and development, quickly and with minimal tissue preparation. The use of the higher resolution reflectance confocal and green fluorescent protein imaging techniques and lower resolution ultrasound were complementary.

Protection against aflatoxin B1-induced cytotoxicity by expression of the cloned aflatoxin B1-aldehyde reductases rat AKR7A1 and human AKR7A3.

The reduction of the aflatoxin B 1 (AFB 1) dialdehyde metabolite to its corresponding mono and dialcohols, catalyzed by aflatoxin B 1-aldehyde reductase (AFAR, rat AKR7A1, and human AKR7A3), is greatly increased in livers of rats treated with numerous chemoprotective agents. Recombinant human AKR7A3 has been shown to reduce the AFB 1-dialdehyde at rates greater than those of the rat AKR7A1. The activity of AKR7A1 or AKR7A3 may detoxify the AFB 1-dialdehyde, which reacts with proteins, and thereby inhibits AFB 1-induced toxicity; however, direct experimental evidence of this hypothesis was lacking. Two human B lymphoblastoid cell lines, designated pMF6/1A2/AKR7A1 and pMF6/1A2, were genetically engineered to stably express AKR7A1 and/or cytochrome P4501A2 (1A2). The pMF6/1A2/AKR7A1 cells were refractory to the cytotoxic effects of 3 ng/mL AFB 1, in comparison to pM6/1A2 cells, which were more sensitive. Diminished protection occurred at higher concentrations of AFB 1 in pMF6/1A2/AKR7A1 cells, suggesting that additional factors were influencing cell survival. COS-7 cells were transfected with either vector control, rat AKR7A1, or human AKR7A3, and the cells were treated with AFB 1-dialdehyde. There was a 6-fold increase in the dialdehyde LC 50, from 66 microM in vector-transfected cells to 400 microM in AKR7A1-transfected cells, and an 8.5-fold increase from 35 microM in vector-transfected cells to 300 microM in AKR7A3-transfected cells. In both cases, this protective effect of the AFAR enzyme was accompanied by a marked decrease in protein adducts. Fractionation of the cellular protein showed that the mitochondria/nuclei and microsomal fractions contained the highest concentration of protein adducts. The levels of human AKR7A3 and AKR7A2 were measured in 12 human liver samples. The expression of AKR7A3 was detectable in all livers and lower than those of AKR7A2 in 11 of the 12 samples. Overall, these results provide the first direct evidence of a role for rat AKR7A1 and human AKR7A3 in protection against AFB 1-induced cytotoxicity and protein adduct formation.

The breast cancer susceptibility gene BRCA1 regulates progesterone receptor signaling in mammary epithelial cells.

The progesterone receptor (PR) plays roles in normal mammary development and breast cancer formation, where it may exert both stimulatory and inhibitory actions. Previously, the breast cancer susceptibility gene product BRCA1 was found to interact with and inhibit the transcriptional activity of estrogen receptor-alpha. In this study, we found that exogenous wild-type BRCA1 inhibited the activity of the PR in transient transfection assays utilizing a mouse mammary tumor virus-Luc reporter. Wild-type BRCA1 inhibited the activity of endogenous PR in human breast cancer cells (T47D and MCF-7) and inhibited the activity of exogenous PR-A, PR-B, and [PR-A plus PR-B] isoforms. On the other hand, knockdown of endogenous BRCA1 using small interfering RNA enhanced the progesterone-stimulated activity of the PR by about 4-fold. We documented an in vivo association of the endogenous BRCA1 with PR isoforms A and B and a direct in vitro interaction between BRCA1 and PR, which was partially mapped. Whereas down-regulation of the coactivator p300 contributes to the BRCA1-mediated repression of estrogen receptor-alpha, this mechanism does not contribute to inhibition of PR activity, because exogenous p300 did not rescue the BRCA1 repression of PR activity. The BRCA1-PR interaction has functional consequences. Thus, we showed that BRCA1 inhibits the expression of various endogenous progesterone-responsive genes and inhibits progesterone-stimulated proliferation of T47D cells. Finally, exogenous progesterone caused an exaggerated proliferative response in the mammary glands of mice harboring a mammary-targeted conditional deletion of the full-length isoform of Brca1. These findings suggest that BRCA1 regulates the activity of progesterone, a major hormone of pregnancy that may also participate in mammary carcinogenesis.

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer.

Loss of full-length Brca1 in mammary epithelial cells of the mouse mammary tumor virus (MMTV)-Cre Brca1 conditional exon 11 deletion mouse model results in the development of mammary adenocarcinomas with similar genetic changes to those found in human BRCA1-mutation-related breast cancers. We used this experimental model to evaluate the chemopreventive effect of tamoxifen on the development of mammary preneoplasia and adenocarcinoma. No protective effects of tamoxifen administration on mammary cancer development were found. Instead, tamoxifen treatment significantly increased rates of mammary epithelial cell proliferation and the prevalence of mammary hyperplasia at 6 months of age. Tamoxifen-exposed mice developed adenocarcinomas at younger ages than control mice and a higher percentage of mice developed adenocarcinomas by 12 months of age. Both whole mouse and tissue culture cell models were used to test if loss of full-length Brca1 was associated with a relative increase in the agonist activity of tamoxifen. Tamoxifen induced increased ductal growth in MMTV-Cre Brca1 conditional mice compared to wild type. Estrogen receptor alpha (ERalpha) expression was downregulated in the tamoxifen-induced hyperplasias. Reducing BRCA1 levels in MCF-7 cells using siRNA resulted in a relative increase in the agonist activity of tamoxifen. Results suggest a model of mammary cancer progression in which loss of full-length Brca1 altered the agonist/antagonist activity of tamoxifen, resulting in tamoxifen-induced mammary epithelial cell proliferation with subsequent loss of ERalpha expression and development of ERalpha-negative hyperplasias and adenocarcinomas.

RANKL/RANK: from bone loss to the prevention of breast cancer.

RANK and RANKL, a receptor ligand pair belonging to the tumour necrosis factor family, are the critical regulators of osteoclast development and bone metabolism. Besides their essential function in bone, RANK and RANKL have also been identified as the key factors for the formation of a lactating mammary gland in pregnancy. Mechanistically, RANK and RANKL link the sex hormone progesterone with stem cell expansion and proliferation of mammary epithelial cells. Based on their normal physiology, RANKL/RANK control the onset of hormone-induced breast cancer through the expansion of mammary progenitor cells. Recently, we and others were able to show that RANK and RANKL are also critical regulators of BRCA1-mutation-driven breast cancer. Currently, the preventive strategy for BRCA1-mutation carriers includes preventive mastectomy, associated with wide-ranging risks and psychosocial effects. The search for an alternative non-invasive prevention strategy is therefore of paramount importance. As our work strongly implicates RANK and RANKL as key molecules involved in the initiation of BRCA1-associated breast cancer, we propose that anti-RANKL therapy could be a feasible preventive strategy for women carrying BRCA1 mutations, and by extension to other women with high risk of breast cancer.

RANKL/RANK control Brca1 mutation- .

Breast cancer is the most common female cancer, affecting approximately one in eight women during their life-time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 (BRCA1) or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable strategy for the possible prevention of breast cancer in BRCA1 mutant patients.

Abnormal Mammary Adipose Tissue Environment of Brca1 Mutant Mice Show a Persistent Deposition of Highly Vascularized Multilocular Adipocytes.

A major challenge to breast cancer research is the identification of alterations in the architecture and composition of the breast that are associated with breast cancer progression. The aim of the present investigation was to characterize the mammary adipose phenotype from Brca1 mutant mice in the expectation that this would shed light on the role of the mammary tissue environment in the early stages of breast tumorigenesis. We observed that histological sections of mammary tissue from adult Brca1 mutant mice abnormally display small, multilocular adipocytes that are reminiscent of brown adipose tissue (BAT) as compared to wildtype mice. Using a marker for BAT, the uncoupling protein 1 (UCP1), we demonstrated that these multilocular adipose regions in Brca1 mutant mice stain positive for UCP1. Transcriptionally, UCP1 mRNA levels in the Brca1 mutant mice were elevated greater than 50-fold compared to age-matched mammary glands from wildtype mice. Indeed, BAT has characteristics that are favorable for tumor growth, including high vascularity. Therefore, we also demonstrated that the multilocular brown adipose phenotype in the mammary fat pad of Brca1 mutant mice displayed regions of increased vascularity as evidenced by a significant increase in the protein expression of CD31, a marker for angiogenesis. This Brca1 mutant mouse model should provide a physiologically relevant context to determine whether brown adipose tissue can play a role in breast cancer development.