| dc.identifier.uri | http://hdl.handle.net/11401/78280 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.type | Dissertation | |
| dcterms.abstract | Disruption of the balanced modulation of reversible tyrosine phosphorylation has been implicated in the etiology of various human cancers. Breast cancer is the most prevalent invasive malignancy among women in the US. It features high heterogeneity, divisible into a variety of subtypes with different molecular profiles and clinical status. Protein Tyrosine Phosphatase Non-receptor 23 (PTPN23) gene resides on chromosomal region 3p21.3, which is hemizygously or homozygously lost in various cancers, including breast cancer of different subtypes. In a loss.of.function PTPome screen, our laboratory previously identified PTPN23 as a suppressor of cell motility and invasion in mammary epithelial and breast cancer cells. The goal of my project has been to characterize the tumor suppressor function of PTPN23. We conducted an analysis of the TCGA database, which illustrated a correlation between low PTPN23 expression and poor survival in breast cancer of various subtypes. Therefore, we investigated the tumor-suppressive function of PTPN23 in an orthotopic transplantation mouse model. Suppression of PTPN23 in Comma 1D? cells induced breast tumors within 56 weeks. In addition, using BT474 cells in a xenograft model we demonstrated that PTPN23 suppression also accelerated tumor progression. In pursuit of the molecular mechanism underlying these effects of PTPN23, we demonstrated hyperphosphorylation of the autophosphorylation site tyrosine in the SRC family kinase (SFK) FYN, as well as elevated phosphorylation of Tyr142 in ?-catenin from PTPN23-depleted primary tumors. Importantly, we demonstrated that PTPN23 recognized FYN as a physiological substrate, functioning as a key phosphatase that normally suppressed the activity of FYN. We validated the underlying mechanism of PTPN23 function in breast tumorigenesis in two different models. First, we demonstrated that tumor outgrowth from PTPN23.deficient BT474 cells was suppressed in a xenograft model in vivo upon treatment with AZD0530, an SFK inhibitor. Furthermore, we demonstrated that double knockout of FYN and PTPN23, via CRISPR/CAS9, also attenuated tumor outgrowth from PTPN23.knockout Cal51 cells. In summary, there have been suggestions in the literature that PTPN23 may lack intrinsic activity and function instead as a “pseudophosphatase”. In contrast, this study demonstrated that PTPN23 was an active phosphatase and that dephosphorylation of the SRC family kinase FYN underlies its tumor.suppressive function in breast tumorigenesis. The ability of PTPN23 to regulate the phosphorylation and activity of FYN highlights the importance of the phosphatase as a regulator of SFK.mediated signaling in breast tumorigenesis and suggests that FYN may be a therapeutic target for breast cancer defined by hemizygous or homozygous loss of PTPN23. | |
| dcterms.available | 2018-06-21T13:38:52Z | |
| dcterms.contributor | Reich Marshall, Nancy C | en_US |
| dcterms.contributor | Carpino, Nicholas | en_US |
| dcterms.contributor | Vakoc, Christopher R R | en_US |
| dcterms.contributor | Egeblad, Mikala | en_US |
| dcterms.creator | Zhang, Siwei | |
| dcterms.dateAccepted | 2018-06-21T13:38:52Z | |
| dcterms.dateSubmitted | 2018-06-21T13:38:52Z | |
| dcterms.description | Department of Molecular Genetics and Microbiology | en_US |
| dcterms.extent | 149 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/78280 | |
| dcterms.issued | 2017-12-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2018-06-21T13:38:52Z (GMT). No. of bitstreams: 1
Zhang_grad.sunysb_0771E_13527.pdf: 8693278 bytes, checksum: 88574317f9ce595e91a4243e32b483d0 (MD5)
Previous issue date: 12 | en |
| dcterms.subject | breast cancer | |
| dcterms.subject | Molecular biology | |
| dcterms.subject | FYN | |
| dcterms.subject | Biochemistry | |
| dcterms.subject | Medicine | |
| dcterms.subject | protein tyrosine phosphatase | |
| dcterms.subject | PTPN23 | |
| dcterms.subject | transplantation animal model | |
| dcterms.title | Regulation of FYN phosphorylation by the PTPN23 tumor suppressor phosphatase in breast tumorigenesis | |
| dcterms.type | Dissertation | |
