Medicine and Health Sciences Commons^™

Nvp-Bez235 Or Jaki Treatment Leads To Decreased Survival Of Examined Gbm And Bbc Cells, Neftali Vazquez, Alma Lopez, Victoria Cuello, Michael W. Persans, Erin Schuenzel, Wendy Innis-Whitehouse, Megan Keniry

Biology Faculty Publications and Presentations

Cancer cells almost universally harbor constitutively active Phosphatidylinositol-3 Kinase (PI3K) Pathway ac-tivity via mutation of key signaling components and/or epigenetic mechanisms. Scores of PI3K Pathway in-hibitors are currently under investigation as putative chemotherapeutics. However, feedback and stem cell mechanisms induced by PI3K Pathway inhibition can lead to reduced treatment efficacy. To address therapeutic barriers, we examined whether JAKi would reduce stem gene expression in a setting of PI3K Pathway inhibition in order to improve treatment efficacy. We targeted the PI3K Pathway with NVP-BEZ235 (dual PI3K and mTOR inhibitor) in combination with the Janus Kinase inhibitor JAKi in glioblastoma (GBM) and …

Small-Molecule Activation Of Lysosomal Trp Channels Ameliorates Duchenne Muscular Dystrophy In Mouse Models, Lu Yu, Xiaoli Zhang, Yexin Yang, Dan Li, Kaiyuan Tang, Zifan Zhao, Wanwan He, Ce Wang, Nirakar Sahoo

Biology Faculty Publications and Presentations

Duchenne muscular dystrophy (DMD) is a devastating disease caused by mutations in dystrophin that compromise sarcolemma integrity. Currently, there is no treatment for DMD. Mutations in transient receptor potential mucolipin 1 (ML1), a lysosomal Ca2+ channel required for lysosomal exocytosis, produce a DMD-like phenotype. Here, we show that transgenic overexpression or pharmacological activation of ML1 in vivo facilitates sarcolemma repair and alleviates the dystrophic phenotypes in both skeletal and cardiac muscles of mdx mice (a mouse model of DMD). Hallmark dystrophic features of DMD, including myofiber necrosis, central nucleation, fibrosis, elevated serum creatine kinase levels, reduced muscle force, impaired motor …

Lack Of Interaction Between Erbb2 And Insulin Receptor Substrate Signaling In Breast Cancer, Sarah M. Farabaugh, Bonita T. Chan, Xiaojiang Cui, Robert Dearth, Adrian V. Lee

Biology Faculty Publications and Presentations

Background: ErbB2 Receptor Tyrosine Kinase 2 (ErbB2, HER2/Neu) is amplified in breast cancer and associated with poor prognosis. Growing evidence suggests interplay between ErbB2 and insulin-like growth factor (IGF) signaling. For example, ErbB2 inhibitors can block IGF-induced signaling while, conversely, IGF1R inhibitors can inhibit ErbB2 action. ErbB receptors can bind and phosphorylate insulin receptor substrates (IRS) and this may be critical for ErbBmediated anti-estrogen resistance in breast cancer. Herein, we examined crosstalk between ErbB2 and IRSs using cancer cell lines and transgenic mouse models.

Methods: MMTV-ErbB2 and MMTV-IRS2 transgenic mice were crossed to create hemizygous MMTV-ErbB2/MMTVIRS2 bigenic mice. Signaling crosstalk …

Metformin And Erlotinib Synergize To Inhibit Basal Breast Cancer, Ying-Ka Ingar Lau, Xing Du, Vinayak Rayannavar, Benjamin Hopkins, Jacquelyn Shaw, Eliana Bessler, Tiffany Thomas, Maira M. Pires, Megan Keniry

Biology Faculty Publications and Presentations

Basal-like breast cancers (BBCs) are enriched for increased EGFR expression and decreased expression of PTEN. We found that treatment with metformin and erlotinib synergistically induced apoptosis in a subset of BBC cell lines. The drug combination led to enhanced reduction of EGFR, AKT, S6 and 4EBP1 phosphorylation, as well as prevented colony formation and inhibited mammosphere outgrowth. Our data with other compounds suggested that biguanides combined with EGFR inhibitors have the potential to outperform other targeted drug combinations and could be employed in other breast cancer subtypes, as well as other tumor types, with activated EGFR and PI3K signaling. Analysis …

Analysis Of High Fat Diet Induced Genes During Mammary Gland Development: Identifying Role Players In Poor Prognosis Of Breast Cancer, Raquel C. Martinez-Chacin, Megan Keniry, Robert Dearth

Biology Faculty Publications and Presentations

Background

Epidemiological studies have shown that consumption of a high-fat diet (HFD) increases the risk of developing breast cancer (BC). Studies in rodents have shown HFD causes changes in the genetic programming of the maturing mammary gland (MG) increasing the susceptibility of developing the disease. Less is known about how HFD induced genes impact BC development. HFD exposure two weeks before conception to six weeks of age was previously shown to dramatically change MG gene expression in 10 week old mice. Therefore, we investigated these differentially expressed HFD-induced genes for their expression in BC using the NKI 295 breast tumor …

Parity-Induced Decrease In Systemic Growth Hormone Alters Mammary Gland Signaling: A Potential Role In Pregnancy Protection From Breast Cancer, Robert K. Dearth, David A. Delgado, Jill K. Hiney, Thushangi Pathiraja, Steffi Oesterreich, Dan Medina, W. Les Dees, Adrian V. Lee

Biology Faculty Publications and Presentations

Early full-term pregnancy is an effective natural protection against breast cancer in both humans and experimental rodents. The protective effect of an early pregnancy is in part linked to changes in circulating hormones that are involved in both normal breast development and breast cancer. For example, a reduction in circulating growth hormone (GH) has been shown to protect rats from carcinogen-induced mammary tumors. We examined the ability of a full-term pregnancy to alter the endocrine GH/IGF-I axis and how this change affected normal mammary gland function in two commonly used rat models (Sprague-Dawley and Wistar-Furth). Circulating GH and IGF-I were …