Problem: Understanding and communicating medical advances driven by basic research, and acquiring foundational skills in critically appraising and communicating translational basic research literature that affects patient care, are challenging for medical students to develop. Approach: The authors developed a mandatory course from 2012 to 2018 at Texas A&M University College of Medicine to address this problem. Medical Student Grand Rounds (MSGR) trains first-year students to find, critically assess, and present primary research literature about self-selected medically relevant topics. With basic science faculty mentoring, students completed milestones culminating in oral presentations. Students learned to search literature databases and then choose a clinical subject using these skills. They outlined the clinical subject area background and a mechanistic research topic into a clinical problem based on deeper evaluation of primary research literature. “Mechanistic” was defined in this context as providing experimental evidence that explained the “how” and “why” underlying clinical manifestations of a disease. Students received evaluations and feedback from mentors about discerning the quality of information and synthesizing information on their topics. Finally, students prepared and gave oral presentations, emphasizing the primary literature on their topics. Outcomes: In the early stages of the course development, students had difficulty critically assessing and evaluating research literature. Mentored training by research-oriented faculty, however, dramatically improved student perceptions of the MSGR experience. Mentoring helped students develop skills to synthesize ideas from basic research literature. According to grades and self-evaluations, students increased proficiency in finding and interpreting research articles, preparing and delivering presentations, and understanding links among basic and translational research and clinical applications. Next Steps: The authors plan to survey fourth-year students who have completed MSGR about their perceptions of the course in the context of clinical experiences in medical school to guide future refinements.

Diet is a critical environmental factor affecting breast cancer risk, and recent evidence shows that dietary exposures during early development can affect lifetime mammary cancer susceptibility. To elucidate the underlying mechanisms, we used our established crossover feeding mouse model, where exposure to a high-fat and high-sugar (HFHS) diet during defined developmental windows determines mammary tumor incidence and latency in carcinogen-treated mice. Mammary tumor incidence is significantly increased in mice receiving a HFHS post-weaning diet (high-tumor mice, HT) compared to those receiving a HFHS diet during gestation (low-tumor mice, LT). The current study revealed that the mammary stem cell (MaSC) population was significantly increased in mammary glands from HT compared to LT mice. Igf1 expression was increased in mammary stromal cells from HT mice, where it promoted MaSC self-renewal. The increased Igf1 expression was induced by DNA hypomethylation of the Igf1 Pr1 promoter, mediated by a decrease in Dnmt3b levels. Mammary tissues from HT mice also had reduced levels of Igfbp5, leading to increased bioavailability of tissue Igf1. This study provides novel insights into how early dietary exposures program mammary cancer risk, demonstrating that effective dietary intervention can reduce mammary cancer incidence.

Dietary exposures at early developmental stages have been shown to program lifetime breast cancer susceptibility. We previously reported that manipulation of gestational and postweaning diets leads to different mammary tumor outcomes in carcinogen-treated mice. The high tumor incidence (HT) groups (average 61.5% tumor incidence) received a low-fat, low-sugar, mildly restricted (12%v/v) (DR) diet during gestation, followed by a high-fat, high-sugar (HF) diet postweaning. Conversely, the low tumor incidence (LT) groups (average 20% tumor incidence) received the HF diet during gestation, followed by the DR diet postweaning. Herein, we extended these findings by demonstrating that HT animals had an expanded mammary stem cell (MaSC) population compared to LT animals before puberty, and this expansion persisted into adulthood. IGF1 expression was increased in mammary stromal cells from HT animals, which promoted the self-renewal capacity of MaSCs in a paracrine fashion. This increased IGF1 expression was programmed prepubertally through DNA hypomethylation of the IGF1 promoter 1, mediated by decreased DNMT3b levels. IGFBP5 mRNA and protein levels were also reduced in mammary tissues from HT animals, indicating an increased bioavailability of tissue IGF1. In association with these changes, mammary tissues from carcinogen-treated HT animals developed an increased proportion of mammary adenosquamous carcinomas compared to carcinogen-treated LT animals. This study provides novel mechanistic insights into how early dietary exposures program mammary cancer risk and tumor phenotypes by increasing IGF1 expression through epigenetic alterations, thereby expanding the MaSC population, resulting in a higher number of carcinogen targets susceptible to transformation in adulthood. Significance Early high-fat dietary exposure programs lifetime mammary cancer susceptibility before puberty through epigenetic alterations of IGF1 promoters and IGF1-mediated paracrine regulation of mammary stem cell homeostasis.