Cells of malignant breast tumors exhibit centrosome defects including an excess number of centrioles, increased microtubule nucleation capacity, and inappropriate phosphorylation of centrosomal proteins, a condition termed 'centrosome amplification Centrosome amplification leads to multipolar mitosis and consequent chromosomal instability, and therefore, is one mechanism by which aneuploidy and phenotypic variability arise in the development of cancer. We propose that centrosome amplification is an early event in the development of breast cancer, and that amplified centrosomes may arise through one of several alternative mechanisms. We propose to characterize the origin of centrosome amplification during the development of breast tumors. We will test the hypothesis that ER and growth factor signaling are mechanistically coupled to centriole separation and centrosome duplication. And finally, we will experimentally disrupt cell cycle progression in normal breast and tumor-derived cell lines to test the hypothesis that the G 1/S and G2/M cell cycle checkpoints are mechanistically coupled to centrosome duplication and that this linkage becomes uncoupled during mammary tumorigenesis. The study of centrosome behavior is of fundamental importance to our understanding of the origin of malignant tumors and may reveal new targets for intervention or prevention of the development of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072836-07
Application #
6752474
Study Section
Pathology B Study Section (PTHB)
Program Officer
Pelroy, Richard
Project Start
1998-01-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
7
Fiscal Year
2004
Total Cost
$271,660
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Leontovich, Alexey A; Jalalirad, Mohammad; Salisbury, Jeffrey L et al. (2018) NOTCH3 expression is linked to breast cancer seeding and distant metastasis. Breast Cancer Res 20:105
Ohmine, Seiga; Salisbury, Jeffrey L; Ingle, James et al. (2018) Aurora-A overexpression is linked to development of aggressive teratomas derived from human iPS cells. Oncol Rep 39:1725-1730
Opyrchal, Mateusz; Gil, Malgorzata; Salisbury, Jeffrey L et al. (2017) Molecular targeting of the Aurora-A/SMAD5 oncogenic axis restores chemosensitivity in human breast cancer cells. Oncotarget 8:91803-91816
Opyrchal, Mateusz; Salisbury, Jeffrey L; Zhang, Shuya et al. (2014) Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ER? expression in initially ER?+ breast cancer cells. PLoS One 9:e96995
Opyrchal, Mateusz; Salisbury, Jeffrey L; Iankov, Ianko et al. (2014) Inhibition of Cdk2 kinase activity selectively targets the CD44?/CD24?/Low stem-like subpopulation and restores chemosensitivity of SUM149PT triple-negative breast cancer cells. Int J Oncol 45:1193-9
D'Assoro, A B; Liu, T; Quatraro, C et al. (2014) The mitotic kinase Aurora--a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ER?(+) breast cancer cells. Oncogene 33:599-610
Leontovich, Alexey A; Salisbury, Jeffrey L; Veroux, Massimiliano et al. (2013) Inhibition of Cdk2 activity decreases Aurora-A kinase centrosomal localization and prevents centrosome amplification in breast cancer cells. Oncol Rep 29:1785-8
Lukasiewicz, Kara B; Greenwood, Tammy M; Negron, Vivian C et al. (2011) Control of centrin stability by Aurora A. PLoS One 6:e21291
D'Assoro, Antonino B; Leontovich, Alexey; Amato, Angela et al. (2010) Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts. Int J Oncol 37:1167-76
Salisbury, Jeffrey L (2010) A centrosome kinase modulates antitumor drug sensitivity. Cancer Cell 18:99-100

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