Preneoplastic stromal cells promote BRCA1-mediated breast tumorigenesis.

Women with germline BRCA1 mutations (BRCA1+/mut) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1+/mut is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1+/mut and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1+/mut stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1+/mut may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.

Accessibility of postgraduate training program information to graduates from US doctor of pharmacy programs holding F-1 visas.

PURPOSE: To evaluate information provided by residency and fellowship programs to graduates of Accreditation Council for Pharmacy Education-accredited doctor of pharmacy programs holding F-1 visas who are seeking postgraduate training opportunities. METHODS: A 2-phase review of all US-based postgraduate year 1 (PGY1) residency and fellowship programs was conducted. In phase 1, program eligibility criteria were reviewed from the residency and fellowship directories published by the American Society of Health-System Pharmacists (ASHP) and American College of Clinical Pharmacy (ACCP). In phase 2, the postgraduate programs' official websites were reviewed for additional information. Each program was evaluated to determine the eligibility of international students with F-1 visa or Optional Practical Training (OPT) status, visa sponsorship and work authorization opportunities, and citizenship requirements. Programs were classified as eligible or noneligible to international students or as not providing sufficient information. Descriptive statistics were used to summarize the data. RESULTS: A total of 1,455 ASHP PGY1 programs and 69 fellowship programs were included in our analysis. In phase 1, there were 3 eligible programs accepting applicants with F-1/OPT status and 377 noneligible programs. In phase 2, there were 10 eligible programs accepting applicants with F-1/OPT status or providing H-1B sponsorship and 410 noneligible programs. Over 70% of programs (phase 1, n = 1,075; phase 2, n = 1,035) were classified as providing no information. None of the fellowship programs were classified as eligible in our review. CONCLUSION: Most residency and fellowship programs did not provide clear eligibility criteria for students with F-1/OPT status. Only a few programs clearly stated that they would accept applicants with F-1/OPT status or provide visa sponsorship to graduates holding F-1 visas.

Patient-derived xenograft culture-transplant system for investigation of human breast cancer metastasis.

Metastasis is a fatal disease where research progress has been hindered by a lack of authentic experimental models. Here, we develop a 3D tumor sphere culture-transplant system that facilitates the growth and engineering of patient-derived xenograft (PDX) tumor cells for functional metastasis assays in vivo. Orthotopic transplantation and RNA sequencing (RNA-seq) analyses show that PDX tumor spheres maintain tumorigenic potential, and the molecular marker and global transcriptome signatures of native tumor cells. Tumor spheres display robust capacity for lentiviral engineering and dissemination in spontaneous and experimental metastasis assays in vivo. Inhibition of pathways previously reported to attenuate metastasis also inhibit metastasis after sphere culture, validating our approach for authentic investigations of metastasis. Finally, we demonstrate a new role for the metabolic enzyme NME1 in promoting breast cancer metastasis, providing proof-of-principle that our culture-transplant system can be used for authentic propagation and engineering of patient tumor cells for functional studies of metastasis.