Abstract/Details

The role of PDK1 in promoting breast cancer susceptibility by activating beta -catenin signaling and modulating the proliferative activity of stem cell antigen-1 (Sca-1)


2006 2006

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Abstract (summary)

PDK1, a 63 KDa serine/threonine kinase, serves as the master switch downstream of growth factor receptor-coupled PI3-Kinase activation. PDK1 phosphorylates and activates AGC kinases, such as Akt and PKC, that promote cell survival, tumorigenesis, invasion, and drug resistance. Our laboratory has previously shown PDK1 to be oncogenic in mouse mammary epithelial cells, forming highly invasive tumors as isografts. This study shows that PDK1 overexpression in human mammary epithelial cells increases EGF-dependent growth and activates beta-catenin signaling in breast cancer cells. PDK1 serves as a novel regulator of stem cell antigen-1 (Sca-1), a glycosylphosphotidylinositol (GPI) anchored protein commonly used as a marker for stem cells. The PI3-Kinase signal cascade has been implicated in the regulation and maintenance of stem and progenitor cells. PDK1-mediated transformation is associated with beta-catenin signal pathway activation and a concomitant decrease in the putative tumor suppressor caveolin-1. Activation of the Wnt pathway promotes tumorigenesis, involving an expansion in the Sca-1+mammary progenitor cells. Furthermore, loss of caveolin-1 and the lipid phosphatase PTEN, the major negative regulator of PI3-Kinase/PDK1 signaling, has also been implicated in a similar expansion of stem cells and tumorigenesis. In cell lines derived from carcinogen-induced tumors, I show that PDK1 regulates Sca-1 expression and promoter activity, independent of IFNgamma stimulation. Dysregulation of interferon signaling occurred downstream of the IFNgamma receptor, shown when dominant negative STAT1 inhibited Sca-1 promoter and KDPDK1 reduced STAT1 levels. Furthermore, treatment of tumor cells with Sca-1 blocking antibody or siRNA decreased cell growth by inducing a G2/M block. Overall, I show that PDK1 plays a critical role in promoting breast cancer susceptibility by activating beta-catenin signaling and modulating the proliferative activity of Sca-1. Targeting PDK1 for cancer therapy would not only target growth factor-mediated signaling, but also a population of Sca-1+cancer stem and early progenitor cells.

Indexing (details)


Subject
Molecular biology;
Cellular biology
Classification
0307: Molecular biology
0379: Cellular biology
Identifier / keyword
Biological sciences; Beta-catenin; Breast cancer; PDK1; Stem cell antigen-1
Title
The role of PDK1 in promoting breast cancer susceptibility by activating beta -catenin signaling and modulating the proliferative activity of stem cell antigen-1 (Sca-1)
Author
Tallapragada, Sruthi
Number of pages
129
Publication year
2006
Degree date
2006
School code
0544
Source
DAI-B 68/07, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780549101826
Advisor
Glazer, Robert I.
University/institution
Georgetown University Medical Center
University location
United States -- District of Columbia
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3270689
ProQuest document ID
304938279
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304938279/abstract
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