Prostate cancer, breast cancer, Cyclin E, the cell cycle, Retinoblastoma/E2F

Proliferation of eukaryotic cells is coordinated by the orderly activation of cyclin-dependent protein kinases. Aberration in the cell cycle regulatory programs is linked to many defects including the development of cancer. Our research has been focused on the cyclin E/RB/E2F pathway which is deregulated in many different tumors, including breast and prostate tumors. RB/E2F transcription factor complex both regulates and is regulated by cyclin E. Cyclin E can phosphorylate RB, resulting in a dissociation of the RB/E2F complex and E2F-dependent transcription. E2F in turn transactivates transcription of the cyclin E gene. Cyclin E has been best studied in beast cancers, where cyclin E overexpression is predictive of hormone therapy failure and of a poor clinical outcome.

There are currently two major projects in the laboratory:

1) The deregulation of cyclin E in breast cancer.
Our studies found that cyclin E overexpression in mammary derived estrogen dependent tumor cells confers a partial resistance to anti-estrogen mediated growth arrest (Dhillon and Mudryj, 2002), but sensitizes cells to cytokine mediated apoptosis (Dhillon and Mudryj, 2003). Most recent studies found that cyclin E overexpression transactivates the intracellular protease calpain 2, thus increasing proteolysis of several proteins including focal adhesion kinase (FAK), c-src, and p53. In a mouse model highly metastatic tumors have higher calpain activity than tumors with a low metastatic potential (Libertini et al, 2005 in press). Our current studies are focused on the role of cyclin E-dependent deregulation of calpain in the etiology and progression of breast cancer.

2) Deregulation of the E2F/RB pathway in prostate cancer.
To define the role of this pathway we have overexpressed E2F1 in androgen-dependent prostate cells. E2F1 overexpressing cells fail to undergo a growth arrest in androgen depleted media, are more sensitive to the apoptotic agent etoposide and have altered expression of multiple genes Libertini et al, 2005, in press). Our studies are designed to decipher the role of the E2F/RB pathway in the development of androgen independence.

independence.

Tepper, C.G., Seldin, M.F., Mudryj, M. (2000) Fas mediated apoptosis of proliferating, transiently growth arrested and senescent normal human fibroblasts. Experimental Cell Research 260, 9-19.

DeBorja, P., Collins, N.K., Du, P., Azizkhan-Clifford, J.C., Mudryj, M. (2001) Cyclin A/CDK2 phosphorylates Sp1 and enhances Sp1 mediated transcription. The EMBO Journal 20:5737-5747.

Ndolo, T., N.K. Dhillon, H. Nguyen, M. Guadalupe, Maria Mudryj, and S. Dandekar. (2002) Simian immunodeficiency virus nef protein delays the progression of CD4 + T cells through G 1/S phase of the cell cycle. Journal of Virology 76:3587-3595.

Dhillon, N.K., and Maria Mudryj. (2002) Ectopic expression of cyclin E in estrogen responsive cells abrogates antiestrogen mediated growth arrest. Oncogene 21:4626-34.

Dhillon, N.K., and Maria Mudryj. (2003) Cyclin E overexpression enhances cytokine-mediated apoptosis in MCF7 breast cancer cells. Genes and Immunity 4, 336-342.

Hau Nguyen, Maria Mudryj, Moraima Guadalupe and Satya Dandekar. ( 2003) Hepatitis C virus core protein expression leads to biphasic regulation of the p21 cdk inhibitor and modulation of hepatocyte cell cycle. Virology 312, 245-253.

Stephen Libertini, Clifford G. Tepper, Moraima Guadalupe, Ying Lu, David M. Asmuth and Maria Mudryj. ( 2005) E2F1 expression in LNCaP prostate cancer cells deregulates androgen dependent growth, suppresses differentiation, and enhances apoptosis. Prostate 66, 70-81.

Stephen J. Libertini, Brian Robinson, Navdeep K. Dhillon, Danielle Glick, Michael George, Satya Dandekar, Jeffrey P. Gregg, Earl Sawai, and Maria Mudryj. (2005) Cyclin E both regulates and is regulated by calpain 2, a protease associated with metastatic breast cancer phenotype. Cancer Research 65, 10700-10708.