Regulation of anoikis and transformation in human breast cancer cells by Bit1 Breast cancer is the most common type of malignancy afflicting women in the United States and around the world. The high mortality rate in this type of cancer warrants a study that can identify key modulators of breast cancer cell survival and malignant phenotype. Since anoikis resistance is an essential step in malignant transformation, re-establishing anoikis sensitivity may be a therapeutic strategy in selectively combating malignant cells. This proposal examines the role of Bit1 (Bcl2 inhibitor of transcription) as a regulator of anoikis resistance and transformation in malignant breast cells. Bit1 is a mitochondrial protein that is released to the cytosol and induces a caspase-independent apoptosis following loss of cell attachment to the extracellular matrix (ECM). Importantly, abrogation of the Bit1 apoptosis pathway contributes not only in anoikis insensitivity but also in the anchorage independent growth capacity of tumor cells (see preliminary results). In this regard, mammary carcinoma cells are likely to bypass the Bit1-mediated pathway to attain anoikis resistance and develop a more aggressive malignant phenotype. Based on published data and preliminary results shown herein, this application proposes the following hypothesis: the anoikis effector Bit1 is a negative regulator or a suppressor of anoikis resistance and malignant phenotype of breast cancer cells, and that activation of Bit1 apoptosis pathway will stimulate anoikis mechanism and attenuate the malignant phenotype associated with breast cancer cells.
The specific aims of this proposal are: 1) to examine the regulation of the malignant phenotype of breast carcinoma cell lines by the Bit1 apoptosis pathway, and 2) to determine the Bit1-regulated signaling pathways that may impact breast cancer cell transformation. The results of this study will provide new information in understanding the molecular mechanisms underlying breast cancer formation and underscore the potential of Bit1 as a novel target in breast cancer therapy.

Public Health Relevance

Regulation of anoikis and transformation in human breast cancer cells by Bit1 Breast cancer is the most common type of malignancy afflicting women in the United States and around the world. Since anoikis resistance is an essential step in malignant transformation, re-establishing anoikis sensitivity may be a therapeutic strategy in selectively combating malignant cells. This proposal examines the potential therapeutic use of Bit1 (Bcl2 inhibitor of transcription) as an inducer of anoikis sensitivity and an inhibitor of transformation in breast cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Pilot Research Project (SC2)
Project #
5SC2CA153382-02
Application #
8061665
Study Section
Special Emphasis Panel (ZGM1-MBRS-7 (GC))
Program Officer
Wali, Anil
Project Start
2010-05-01
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$108,559
Indirect Cost
Name
Xavier University of Louisiana
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
020857876
City
New Orleans
State
LA
Country
United States
Zip Code
70125
Jenning, Scott; Pham, Tri; Ireland, Shubha Kale et al. (2013) Bit1 in anoikis resistance and tumor metastasis. Cancer Lett 333:147-51
Brunquell, Chris; Biliran, Hector; Jennings, Scott et al. (2012) TLE1 is an anoikis regulator and is downregulated by Bit1 in breast cancer cells. Mol Cancer Res 10:1482-95