Fibroblast growth factor (FGF) cooperates with the Wnt/beta-catenin pathway to promote mammary tumorigenesis. To investigate the mechanisms involved in FGF/Wnt cooperation, we genetically engineered a model of inducible FGF receptor (iFGFR) signaling in the context of the well-established mouse mammary tumor virus-Wnt-1 transgenic mouse. In the bigenic mice, iFGFR1 activation dramatically enhanced mammary tumorigenesis. Expression microarray analysis did not show transcriptional enhancement of Wnt/beta-catenin target genes but instead showed a translational gene signature that also correlated with elevated FGFR1 and FGFR2 in human breast cancer data sets. Additionally, iFGFR1 activation enhanced recruitment of RNA to polysomes, resulting in a marked increase in protein expression of several different Wnt/beta-catenin target genes. FGF pathway activation stimulated extracellular signal-regulated kinase and the phosphorylation of key translation regulators both in vivo in the mouse model and in vitro in a human breast cancer cell line. Our results suggest that cooperation of the FGF and Wnt pathways in mammary tumorigenesis is based on the activation of protein translational pathways that result in, but are not limited to, increased expression of Wnt/beta-catenin target genes (at the level of protein translation). Further, they reveal protein translation initiation factors as potential therapeutic targets for human breast cancers with alterations in FGF signaling.
p190-B Rho GTPase activating protein is essential for mammary gland development because p190-B deficiency prevents ductal morphogenesis. To investigate the role of p190-B during distinct stages of mammary gland development, tetracycline-regulatable p190-B-overexpressing mice were generated. Short-term induction of p190-B in the developing mammary gland results in abnormal terminal end buds (TEBs) that exhibit aberrant budding off the neck, histological anomalies, and a markedly thickened stroma. Overexpression of p190-B throughout postnatal development results in increased branching, delayed ductal elongation, and disorganization of the ductal tree. Interestingly, overexpression of p190-B during pregnancy results in hyperplastic lesions. Several cellular and molecular alterations detected within the aberrant TEBs may contribute to these phenotypes. Signaling through the IGF pathway is altered, and the myoepithelial cell layer is discontinuous at sites of aberrant budding. An increase in collagen and extensive infiltration of macrophages, which have recently been implicated in branching morphogenesis, is observed in the stroma surrounding the p190-B-overexpressing TEBs. We propose that the stromal response, disruption of the myoepithelial layer, and alterations in IGF signaling in the p190-B-overexpressing mice impact the TEB architecture, leading to disorganization and increased branching of the ductal tree. Moreover, we suggest that alterations in tissue architecture and the adjacent stroma as a consequence of p190-B overexpression during pregnancy leads to loss of growth control and the formation of hyperplasia. These data demonstrate that precise control of p190-B Rho GTPase-activating protein activity is critical for normal branching morphogenesis during mammary gland development.
Thirty percent of human breast cancers have amplification of ERBB2, often in conjunction with mutations in p53. The most common p53 mutation in human breast cancers is an Arg-to-His mutation at codon 175, an allele that functions in a dominant oncogenic manner in tumorigenesis assays and is thus distinct from loss of p53. Transgenic mice expressing mouse mammary tumor virus-driven neu transgene (MMTV-neu) develop clonal mammary tumors with a latency of 234 days, suggesting that other events are necessary for tumor development. We have examined the role of mutations in p53 in tumor development in these mice. We have found that 37% of tumors arising in these mice have a missense mutations in p53. We have directly tested for cooperativity between neu and mutant p53 in mammary tumorigenesis by creating bitransgenic mice carrying MMTV-neu and 172Arg-to-His p53 mutant (p53-172H). In these bitransgenic mice, tumor latency is shortened to 154 days, indicating strong cooperativity. None of the nontransgenic mice or the p53-172H transgenic mice developed tumors within this time period. Tumors arising in the p53-172H/neu bitransgenic mice were anaplastic and aneuploid and exhibited increased apoptosis, in distinction to tumors arising in p53-null mice, in which apoptosis is diminished. Further experiments address potential mechanisms of cooperativity between the two transgenes. In these bitransgenic mice, we have recapitulated two common genetic lesions that occur in human breast cancer and have shown that p53 mutation is an important cooperating event in neu-mediated oncogenesis.
This study investigated the teaching experiences of three school personnel at a public high school during the 2020–2021 school year as they implemented a unique science, technology, engineering, arts, and math (STEAM) unit with in-person and virtual students in their engineering classes during the Covid-19 pandemic. A research team interviewed two teachers and one administrator at the school to better understand the nuances of pre-college engineering during a pandemic year and how changes in school and district policy affected the instructional delivery of STEAM projects. Narrative analytic methods were utilized to understand each participant's experience and an inductive content thematic approach was used to develop the findings. The participants described varied experiences navigating instruction during the pandemic, particularly when adapting hands-on STEAM projects for virtual or hybrid teaching. All three participants thought deeply about how to best meet the needs of students while attempting to support equitable instruction. The findings of this study indicate that pre-college engineering in the pandemic was challenging for the participants, but not impossible, and that this setting was an appropriate context for STEAM projects that provided students with a mechanism for collaboration and engagement.
Abstract Some of the earliest evidence implicating both Wnt and FGF signaling in mammary tumorigenesis came from the observation of tumors in mouse mammary tumor virus (MMTV)- infected mice. Tumors arising from MMTV proviral insertion often exhibited preferential activation of Wnt and FGF pathway members. Interestingly, tumors with MMTV-induced expression of these FGF pathway ligands also showed MMTV-induced activation of Wnt pathway members, and functional cooperativity of MMTV-driven Wnt 1 and Fgf-3 transgenes in mammary tumorigenesis was observed. High throughput MMTV insertional mutagenesis studies have indicated that activation of Wnt and FGF pathway components is the most common occurrence in resulting tumors, providing definitive genetic proof for the cooperativity between these two pathways. Unraveling the complexity of these pathways in the context of development and tumorigenesis remains an evolving challenge. While the Wnt/ß-catenin cascade plays a central role in a range of biological processes, it has emerged as a key regulator of stem cell dynamics in multiple tissues, including the mammary gland. Significant evidence now implicates the Wnt/ß-catenin pathway in uncontrolled self-renewal of cancer stem cells and their associated radiation resistance during treatment. In the mammary gland, localized Wnt signaling most likely plays a critical role in regulating oriented cell division and cell fate. As with many signaling pathways, this is not an “on and off switch”, but is instead influenced by the level and duration of the signaling event. There are also Wnt-mediated ß-catenin-independent pathways, known as noncanonical Wnt cascades. For instance, noncanonical Wnt signaling through the receptor Ror2 helps to specify the extent and location of canonical Wnt/ß-catenin signaling. With regard to FGF signaling, FGFR1 and FGFR2, the two primary FGFRs expressed in mouse mammary epithelium, also are critical for mammary stem cell maintenance. Cooperation of the FGF and Wnt pathways in mammary tumorigenesis is based in part on the activation of protein translational pathways that result in, but are not limited to, increased expression of Wnt/β-catenin target genes at the level of protein translation. Lastly, Wnt and Fgf ligands can be regulated by systemic steroid hormones and act in a paracrine manner to influence mammary stem cells, providing another layer to the signaling hierarchy. Supported by grant NIH-CA16303. Citation Format: Jeffrey M. Rosen, Xue Bin, Kevin Roarty. Wnt and Fgf signaling in mammary stem cells and breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA13.
