Breast cancer is a leading cause of cancer death among women. Current strategies to combat breast cancer mainly target late stage malignancies to extend lifespan;consequently, they often fail to result in disease free survival. While detection of pre-malignant lesions is increasingly accurate, the inability to predict which precancerous lesions lead to neoplastic growth has impeded efforts to identify patients that are likely to develop aggressive neoplasms or drugs to prevent this. This study addresses this issue by defining how the early loss of cellular differentiation is coordinated with the induction of aberrant proliferation by the adaptor protein Amot. Because the breakdown of the apical polarity is one of the earliest essential steps for cells to be sensitized to pro-growth signaling, such studies may explain how highly proliferative breast cancer cells that utilize ErbB type receptor tyrosine kinases for growth are formed. Our model relating these effects to a cellular mechanism posits that polarity proteins induce the prolonged activation of MAPKs. This is consistent with several reports that Ras and Erk1/2 must be targeted to endosomes to undergo prolonged activation that is required for cellular proliferation. The implications of this model for promoting the formation and progression of ErbB2 and triple negative type breast cancers will be investigated.
A majority of the 40,000 mortalities from breast cancer each year follow therapeutic strategies that target late stage malignant tumors. The premise of this proposal is that long-term survival could be substantially improved if early hyperplastic lesions were prevented from developing into aggressive cancers;a process that is mainly characterized by the loss of epithelial architecture and aberrant cellular accumulation. To this end, this study will investigate a novel mechanism whereby loss of cellular shape directly regulates cell growth to promote early initiation of cellular proliferation and invasiveness.
|Wang, Haiyan; Cai, Shanbao; Bailey, Barbara J et al. (2017) Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist. J Neurosurg 126:446-459|
|Zeng, Li-Fan; Zhang, Ruo-Yu; Yu, Zhi-Hong et al. (2014) Therapeutic potential of targeting the oncogenic SHP2 phosphatase. J Med Chem 57:6594-609|
|Luo, Na; Conwell, Michael D; Chen, Xingjuan et al. (2014) Primary cilia signaling mediates intraocular pressure sensation. Proc Natl Acad Sci U S A 111:12871-6|
|Adler, Jacob J; Heller, Brigitte L; Bringman, Lauren R et al. (2013) Amot130 adapts atrophin-1 interacting protein 4 to inhibit yes-associated protein signaling and cell growth. J Biol Chem 288:15181-93|
|Adler, Jacob J; Johnson, Derrick E; Heller, Brigitte L et al. (2013) Serum deprivation inhibits the transcriptional co-activator YAP and cell growth via phosphorylation of the 130-kDa isoform of Angiomotin by the LATS1/2 protein kinases. Proc Natl Acad Sci U S A 110:17368-73|
|Nguyen, H B; Babcock, J T; Wells, C D et al. (2013) LKB1 tumor suppressor regulates AMP kinase/mTOR-independent cell growth and proliferation via the phosphorylation of Yap. Oncogene 32:4100-9|
|Luo, Na; West, Callah C; Murga-Zamalloa, Carlos A et al. (2012) OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Hum Mol Genet 21:3333-44|
|Jiang, Sixin; Wells, Clark D; Roach, Peter J (2011) Starch-binding domain-containing protein 1 (Stbd1) and glycogen metabolism: Identification of the Atg8 family interacting motif (AIM) in Stbd1 required for interaction with GABARAPL1. Biochem Biophys Res Commun 413:420-5|
|Olhovsky, Marina; Williton, Kelly; Dai, Anna Yue et al. (2011) OpenFreezer: a reagent information management software system. Nat Methods 8:612-3|
|Ranahan, William P; Han, Zhang; Smith-Kinnaman, Whitney et al. (2011) The adaptor protein AMOT promotes the proliferation of mammary epithelial cells via the prolonged activation of the extracellular signal-regulated kinases. Cancer Res 71:2203-11|
Showing the most recent 10 out of 11 publications