Browsing by Author "Young, Jeanette"

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    Cdc42 overexpression induces hyperbranching in the developing mammary gland by enhancing cell migration
    (Springer Nature, 2013) Bray, Kristi; Gillette, Melissa; Young, Jeanette; Loughran, Elizabeth; Hwang, Melissa; Sears, James Cooper; Vargo-Gogola, Tracy; Biochemistry and Molecular Biology, School of Medicine
    Introduction: The Rho GTPase Cdc42 is overexpressed and hyperactivated in breast tumors compared to normal breast tissue. Cdc42 regulates key processes that are critical for mammary gland morphogenesis and become disrupted during the development, progression, and metastasis of breast cancer. However, the contribution of Cdc42 to normal and neoplastic mammary gland development in vivo remains poorly understood. We were therefore interested in investigating the effects of Cdc42 overexpression on mammary gland morphogenesis as a first step toward understanding how its overexpression may contribute to mammary tumorigenesis. Methods: We developed a tetracycline-regulatable Cdc42 overexpression mouse model in which Cdc42 can be inducibly overexpressed in the developing mammary gland. The effects of Cdc42 overexpression during postnatal mammary gland development were investigated using in vivo and in vitro approaches, including morphometric analysis of wholemounted mammary glands, quantification of histological markers, and primary mammary epithelial cell (MEC) functional and biochemical assays. Results: Analysis of Cdc42-overexpressing mammary glands revealed abnormal terminal end bud (TEB) morphologies, characterized by hyperbudding and trifurcation, and increased side branching within the ductal tree. Quantification of markers of proliferation and apoptosis suggested that these phenotypes were not due to increased cell proliferation or survival. Rather, Cdc42 overexpressing MECs were more migratory and contractile and formed dysmorphic, invasive acini in three-dimensional cultures. Cdc42 and RhoA activities, phosphorylated myosin light chain, and MAPK signaling, which contribute to migration and invasion, were markedly elevated in Cdc42 overexpressing MECs. Interestingly, Cdc42 overexpressing mammary glands displayed several features associated with altered epithelial-stromal interactions, which are known to regulate branching morphogenesis. These included increased stromal thickness and collagen deposition, and stromal cells isolated from Cdc42 overexpressing mammary glands exhibited elevated mRNA expression of extracellular matrix proteins and remodeling enzymes. Conclusions: These data suggest that Cdc42 overexpression disrupts mammary gland branching morphogenesis by altering Rho GTPase and MAPK signaling, leading to increased MEC contractility and migration in association with stromal alterations. Our studies provide insight into how aberrant Cdc42 expression may contribute to mammary tumorigenesis.
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    Determinants of Risk-Aligned Bladder Cancer Surveillance—Mixed-Methods Evaluation Using the Tailored Implementation for Chronic Diseases Framework
    (American Society of Clinical Oncology, 2022) Schroeck, Florian R.; Ismail, A. Aziz Ould; Perry, Grace N.; Haggstrom, David A.; Sanchez, Steven L.; Walker, DeRon R.; Young, Jeanette; Zickmund, Susan; Zubkoff, Lisa; Medicine, School of Medicine
    Purpose: For many patients with cancer, the frequency of surveillance after primary treatment depends on the risk for cancer recurrence or progression. Lack of risk-aligned surveillance means too many unnecessary surveillance procedures for low-risk patients and not enough for high-risk patients. Using bladder cancer as an example, we examined whether practice determinants differ between Department of Veterans Affairs sites where risk-aligned surveillance was more (risk-aligned sites) or less common (need improvement sites). Methods: We used our prior quantitative data to identify two risk-aligned sites and four need improvement sites. We performed semistructured interviews with 40 Veterans Affairs staff guided by the Tailored Implementation for Chronic Diseases framework that were deductively coded. We integrated quantitative data (risk-aligned site v need improvement site) and qualitative data from interviews, cross-tabulating salient determinants by site type. Results: There were 14 participants from risk-aligned sites and 26 participants from need improvement sites. Irrespective of site type, we found a lack of knowledge on guideline recommendations. Additional salient determinants at need improvement sites were a lack of resources ("the next available without overbooking is probably seven to eight weeks out") and an absence of routines to incorporate risk-aligned surveillance ("I have my own guidelines that I've been using for 35 years"). Conclusion: Knowledge, resources, and lack of routines were salient barriers to risk-aligned bladder cancer surveillance. Implementation strategies addressing knowledge and resources can likely contribute to more risk-aligned surveillance. In addition, reminders for providers to incorporate risk into their surveillance plans may improve their routines.