Recipient Organization
UNIV OF MASSACHUSETTS
(N/A)
AMHERST,MA 01003
Performing Department
Dept: Nutrition
Non Technical Summary
The early years of life--from childhood through adolescence--are a critical time for setting the foundation for lifelong health. While many studies have looked at nutrition affects during gestation and lactation, there's much less research on how what children and teens eat impacts their health as adults. This is especially concerning, because national dietary data shows that most children and teens in the U.S. have poor diets--scoring below 55 out of 100 on the Healthy Eating Index. Breast cancer is the most common cancer among females in the United States, with over 310,000 new cases expected in 2024 alone. It also remains the second leading cause of cancer-related deaths in females. While advances in screening and treatment have helped reduce death rates since 1990, the number of new breast cancer cases continues to rise--especially among younger females. Alarmingly, about half of female who die from breast cancer in the U.S. today are under the age of 45. One key gap in our understanding is why breast cancer in younger female has been increasing over the past 50 years. Our project aims to explore whether poor Western-style diet (WSD) during childhood and adolescence plays a role in this trend--and if improving early-life nutrition could help prevent breast cancer later on. In our early studies using animal models, we found that eating a high-fat diet during youth led to long-lasting changes in the gut microbiome and in breast tissue--changes that may increase the risk of developing breast cancer later in life. These findings suggest that the rise in breast cancer among young female may be linked, at least in part, to the increasing popularity of Western-style diets, which are often high in fat and low in fiber and essential nutrients. Beans are a powerful, nutrient-rich food that can help improve the quality of WSD. They contain fiber, protein, and other important nutrients that many people in Western countries don't get enough of. However, we still don't know enough how effective to incorporate beans into WSD for children and adolescents and thereby to promote breast health, reducing the risk of early-onset breast cancer. This project will focus on three main goals: 1) To examine how adding beans to a Western-style diet during childhood affects the gut and breast health later in life; 2) To investigate whether this dietary change can reduce the risk of developing breast cancer in adulthood; and 3) To understand the role of the gut microbiome in connecting early-life diet to breast health outcomes. By exploring these questions, we hope to develop practical, science-based dietary strategies to help reduce the risk of breast cancer--starting with better nutrition in the early years of life.
Animal Health Component
60%
Research Effort Categories
Basic
30%
Applied
60%
Developmental
10%
Goals / Objectives
The early stages of life represent a crucial window of opportunity to have positive effects on later health. While there is significant research on the impact of nutrition during the prenatal period and the first 24 months, research on the impact of nutrition during the prenatal period and the first 24 months, research on the impact of nutrition during childhood and adolescence on health later in lifeis highly lacking. However, according to the Dietary Guidelines for Americans, childhood and adolescence are the most vulnerable periods across the lifespan, with an average score of Health Eating Index less than 55 over a total of 100 points. Breast cancer (BC) is the most common cancer in women in the United States, with approximately 310,720 new cases estimated in 2024, accounting for 32% of all new cases of cancer in women. It represents the second most common cause of death from cancer in women in the United States. Despite the fact that BC mortality rates have steadily decreased since 1990 due to improvements in screening and therapeutic practice, BC incidence rates continue to rise. Particularly, the incidence of young-onset BC, generally defined as BC diagnosed in adults <50 years of age, has significantly increased in the past ~50 years. The latest available incidence data from the Centers for Disease Control and Prevention (CDC) indicate that currently about half of women who died of BC in the United States were younger than 45 years. A critical knowledge gap lies in comprehending the etiology of the increasing incidence of BC, especially the emerging young-onset BC. The overall objective of this proposal is to address this gap by investigating the influence of nutrition during the vulnerable but understudied window of childhood and adolescence on the mammary microenvironment later in life. The long-term goal of this proposal is to develop early-life dietary strategies that can be utilized to improve breast health and thereby effectively reduce the escalating rate of the emerging young-onset BC. In our preliminary studies, by using an animal model that replicates human lifespan, we examined the effects of early-life exposure to a high-fat diet, equivalent to childhood and adolescence, on breast health at the later stage of life. Our findings revealed that, immediately after 8-wk high-fat diet feeding during early life, a great number of microbial taxa (>50) were significantly altered, and after transitioning back to the normal lifecycle maintenance diet for 12 wks, about a half of those taxa (25) remain changed. Our data further demonstrated that a high-fat diet during early life significantly modified the mammary metabolic and inflammatory microenvironment in favor of breast tumorigenesis later in life. Based on these intriguing findings, our central hypothesis is that the increasing prevalence of young-onset BC in middle adulthood in US over the past five decades can be attributed, at least in part, to the shift towards a Western-style Diet (WSD), particularly during the vulnerable periods of childhood and adolescence. As beans provide a unique dietary composition rich in various nutrients often lacking in WSD 30-33, they can serve as excellent complementary wholefoods to enhance the quality of WSD and promote breast health. However, our current knowledge is still limited regarding the mechanisms, effectiveness, and practical strategies to incorporate e beans into WSD, thereby to improve its quality and promote breast health. The objectives of this proposal are: Objective #1: To assess the long-term effects of the integration of beans into a Western-style diet during early life on the gut microbiome and the mammary microenvironment later in life. Objective #2: To determine the impact of incorporating beans into Western-style diet during early life on the development of young-onset breast cancer in middle adulthood. Objective #3: To elucidate the involvement of the gut microbiome in modulating the influence of nutrition during early life on breast health later in life.
Project Methods
This project proposed pre-clinical animal studies to investigate to what extent incorporating beans into WSD in early life improves the mammary microenvironment (Aim #1), attenuates the development of young-onset BC (Aim #2), and shifts the gut microbiome (Aim #3). Especially, a wholefood approach will be used to explore the potential of beans in improving the quality of Western-style diet (WSD) and thereby diminishing the risk of early-onset breast cancer in females. We have intentionally selected two types of beans: great northern bean, which has the highest fiber content among commonly consumed beans in the United States, and soybean, which is popularly consumed in Asian countries where people enjoy a low incidence of BC. The 1st animal study in this proposal aims to test our hypothesis that early-life WSD exacerbates, whereas the addition of beans improves, breast health. The 2nd animal study will leverage a genetically-engineered BC model (MMTV-Erbb2) is to test the hypothesis that the incorporation of beans into the WSD during early life attenuates the development of young-onset BC later in life in the middle adulthood. Lastly, the role of gut microbiome in mediating the connection between early-life intake of beans and breast health - particularly the risk of early-onset breast cancer - will be investigated. Experimental methods include 1) Inflammatory cytokine profiling: Inflammatory status will be examined both systematically (blood) and locally (inguinal mammary tissue). A systematic inflammatory cytokine profile with 10 inflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-?, MCP-1) will be examined using a high-performance, electrochemiluminescent immunoassay (Meso Scale Discovery System®, MSD). 2) Measurement of metabolites and hormones: As the metabolites and hormones in the mammary tissue directly affect breast cancer cell growth, the expressions of a group of metabolic genes, including Pparγ, Cebpα, Adiponectin (Adipoq), Adiponectin Receptor 1 (AipoqR1) and Adiponectin Receptor 2 (AipoqR2), and a panel of hormone-related regulators including Aromatase, Estrogen Receptor α and β (Erα and Erβ), Prostaglandin-endoperoxide synthase 2 (Cox2), and Prosta-glandin E2 receptors (PtgeR1 and PtgeR2) will be measured in inguinal mammary tissue. The PI has the ViiA™ 7 real time PCR machine (Life Technologies) in his laboratory, which can read both 96 and 384 plates. Gene expressions of these genes will be measured using this instrument. 3) Gut microbiome: 16S rRNA sequencing will be performed on the fecal contents. The 16S sequencing will be performed in my collaborator's (Dr. Yanjiao Zhou's) laboratory in the University of Connecticut Health Center. Dr. Zhou is a lead analyst in gut microbiome and her lab is capable to provide necessary resources and technical supported needed microbiome sequencing and analysis. 4) Cellular proliferation and apoptosis analysis: Cell cycle kinetics, measured by indices of proliferation and apoptosis, will be determined by immunohistochemical quantification of Ki-67 and cleaved caspase-3, respectively. 5) Tumor parameters: The primary endpoints for the 2nd study are tumors. After sacrifice, mammary gland tumors will be removed, counted, and measured. The tumor incidence (% of animals with tumors in each group), tumor multiplicity (# of tumors in each mouse), and tumor size (the average diameters of tumors) will be determined accordingly. Efforts will be reflected in the dissemination of science-based knowledge. As outlined in the Products and Outcomes Sections, These efforts include 1) Scientific Publications: This represents the primary output. We anticipate producing 2-4 peer-reviewed articles in leading journals focused on food, nutrition, and health. 2) Instructional Impact: During the implementation of this project, it will offer training opportunities for undergraduate and graduate students, as well as research scholars, thereby contributing to the education of future nutritionists and dietitians. Findings from the project may also be integrated into curriculum development for nutrition courses. 3) Service and Outreach: Stakeholders in the bean agriculture sector and healthcare providers, particularly those focused on the health of children and adolescents, will benefit from the dissemination of results through scientific publications and conference presentations. The success of the project will be evaluated primarily based on the number of peer-reviewed publications, conference presentations, and the number of students and researchers trained. In terms of the milestones, we expect that the animal study for Aim #1 will be completed within the first two years, and thereby the 1st publication and conference presentations will are expected after the completion of the first animal study. Aim #2 will be completed in year 2-3 and Aim #3 will be completed in year 3-4. An additional 1-3 publications and conference presentations are anticipated as these aims progress.