The long-range goal of my research is to uncover the nature of the cancer stem cells, and to design therapeutic approaches that can specifically target these cells for the treatment of breast cancers. The objective of this application is to establish the expression pattern of NS and Ngp1 in breast cancer cells, determine the growth phenotype and gene expression profile of NS- and Ngp1-expressing cells, and provide experimental evidence that demonstrates the role of NS+ cells in breast tumorigenesis. The central hypothesis is that NS and Ngp1 are preferentially expressed by the stem-like cells in breast tumors, and that these cells are responsible for the rapid growth, drug resistance, and high metastasis of malignant breast cancers. The rationale is that cancer stem cells, which are responsible for the high growth rate and drug resistance of malignant breast cancers, share common molecules such as NS and Ngp1 with somatic stem cells to drive the self-renewing machinery. Therefore, eliminating NS-expressing breast cancer cells will inhibit tumor initiation and progression. To accomplish the overall objective of this proposal, three specific aims will be pursued.
The first aim i s to establish the expression pattern of NS and Ngp1 in normal breast tissues and breast cancer cells.
The second aim i s to determine the cellular and molecular properties of those NS- and Ngp1-expressing cells by genetically marking these cells with living color proteins and purifying them by flow cytometry.
The third aim i s to determine the role of NS+ cells in the development, progression, and recurrence of breast tumors by evaluating the consequences of their elimination. An inducible cell ablation system will be employed to target the NS+ cells in transgenic animals. These results will provide the much-needed justification for the use of stem cell-targeting therapy in cancer treatment, and valuable information for developing new pharmacological and genetic therapies that can specifically target these cancer stem cells in order to cure advanced breast carcinomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA113750-04
Application #
7387336
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2005-04-01
Project End
2010-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
4
Fiscal Year
2008
Total Cost
$245,225
Indirect Cost
Name
Texas A&M University
Department
Type
Schools of Medicine
DUNS #
835607441
City
College Station
State
TX
Country
United States
Zip Code
77845
Huang, Guanqun; Meng, Lingjun; Tsai, Robert Y L (2015) p53 Configures the G2/M Arrest Response of Nucleostemin-Deficient Cells. Cell Death Discov 1:
Tsai, Robert Y L (2015) Pluripotency Versus Self-Renewal of ES Cells: Two Sides of the Same Coin or More? Stem Cells 33:2358-9
Lin, Tao; Meng, Lingjun; Lin, Tsung-Chin et al. (2014) Nucleostemin and GNL3L exercise distinct functions in genome protection and ribosome synthesis, respectively. J Cell Sci 127:2302-12
Meng, Lingjun; Lin, Tao; Peng, Guang et al. (2013) Nucleostemin deletion reveals an essential mechanism that maintains the genomic stability of stem and progenitor cells. Proc Natl Acad Sci U S A 110:11415-20
Meng, Lingjun; Hsu, Joseph K; Zhu, Qubo et al. (2011) Nucleostemin inhibits TRF1 dimerization and shortens its dynamic association with the telomere. J Cell Sci 124:3706-14
Meng, L; Hsu, J K; Tsai, R Y L (2011) GNL3L depletion destabilizes MDM2 and induces p53-dependent G2/M arrest. Oncogene 30:1716-26
Lin, Tao; Meng, Lingjun; Li, Yi et al. (2010) Tumor-initiating function of nucleostemin-enriched mammary tumor cells. Cancer Res 70:9444-52
Lo, An-Chi; Soliman, Amr S; Khaled, Hussein M et al. (2010) Lifestyle, occupational, and reproductive factors and risk of colorectal cancer. Dis Colon Rectum 53:830-7
Pederson, Thoru; Tsai, Robert Y L (2009) In search of nonribosomal nucleolar protein function and regulation. J Cell Biol 184:771-6
Tsai, Robert Y L; Meng, Lingjun (2009) Nucleostemin: a latecomer with new tricks. Int J Biochem Cell Biol 41:2122-4

Showing the most recent 10 out of 20 publications