deficiency modulates the stromal environment in the pretumorigenic rat mammary gland.

Background: Neurofibromin, coded by the tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1)-a tumor predisposition syndrome caused by a germline mutation-have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which mutations lead to breast cancer tumorigenesis is not well understood.

Ex Vivo Patient-Derived Explant Model for Neurofibromatosis Type 1-Related Cutaneous Neurofibromas.

Cutaneous neurofibromas (CNFs) are benign tumors that occur in the dermis of individuals with the inherited tumor predisposition disorder, neurofibromatosis type 1. CNFs cause disfigurement, pain, burning, and itching, resulting in substantially reduced QOL in patients with neurofibromatosis type 1. CNFs are benign tumors that exhibit cellular and molecular heterogeneity, making it difficult to develop tractable in vitro or in vivo models.

NF1 deficiency drives metabolic reprogramming in ER+ breast cancer.

Objective: NF1 is a tumor suppressor gene and its protein product, neurofibromin, is a negative regulator of the RAS pathway. NF1 is one of the top driver mutations in sporadic breast cancer such that 27 % of breast cancers exhibit damaging NF1 alterations. NF1 loss-of-function is a frequent event in the genomic evolution of estrogen receptor (ER)+ breast cancer metastasis and endocrine resistance.

Dissecting the Rat Mammary Gland: Isolation, Characterization, and Culture of Purified Mammary Epithelial Cells and Fibroblasts.

With the advent of CRISPR-Cas and the ability to easily modify the genome of diverse organisms, rat models are being increasingly developed to interrogate the genetic events underlying mammary development and tumorigenesis. Protocols for the isolation and characterization of mammary epithelial cell subpopulations have been thoroughly developed for mouse and human tissues, yet there is an increasing need for rat-specific protocols. To date, there are no standard protocols for isolating rat mammary epithelial subpopulations.

Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling.

Benign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion.

Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D.

Ras GTPases are mutated at codons 12, 13, and 61, with different frequencies in KRas, HRas, and NRas and in a cancer-specific manner. The G13D mutant appears in 25% of KRas-driven colorectal cancers, while observed only rarely in HRas or NRas. Structures of Ras G13D in the three isoforms show an open active site, with adjustments to the D13 backbone torsion angles and with disconnected switch regions.

deficiency correlates with estrogen receptor signaling and diminished survival in breast cancer.

The key negative regulatory gene of the RAS pathway, , is mutated or deleted in numerous cancer types and is associated with increased cancer risk and drug resistance. Even though women with neurofibromatosis (germline mutations) have a substantially increased breast cancer risk at a young age and is commonly mutated in sporadic breast cancers, we have a limited understanding of the role of in breast cancer. We utilized CRISPR-Cas9 gene editing to create rat models to evaluate the effect of deficiency on tumorigenesis.