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ESTROGEN REGULATION OF BREAST CANCER CELL PROLIFERATION

Susan Conrad

1 July 1998 - 30 April 2004
NATIONAL CANCER INSTITUTE
Total Funding: $ 814,427

The long term goals of this research are to understand how estrogen and antiestrogens regulate human breast cancer cell proliferation, an how cells that initially require estrogen to proliferate eventually become estrogen independent and antiestrogen resistant. Attaining these goals is critical, since the development of estrogen independence and antiestrogen resistance is a major cause of treatment failure in breast cancer patients. On approach that will be taken is to compare regulation of the intracellular cyclin/CDK pathway that controls cell proliferation in the estrogen dependent breast cancer cell line MCF-7, in estrogen independent and antiestrogen resistant derivatives of MCF-7, and in a panel of other ER+ and ER- breast cancer cell lines. In addition, experiments will be carried out to determine whether perturbing the cyclin/CDK pathway can directly convert MCF-7 cells to estrogen independence and/or estrogen resistance. In Aim I, the regulation of protein levels and CDK activity will be compared in the cell lines described above. In Aims II-IV, the cyclin/CDK pathway will be disrupted in a variety of ways including inhibition of cyclin/CDK activity, inhibition of RB function, and overexpression of cyclin genes, and the effects of these perturbations on hormone dependence of fMCF-7 cells will be examined. These studies will identify important targets of estrogen and antiestrogen action, and suggest possible mechanisms by which breast tumors can become estrogen independent and antiestrogen resistant.

7 Resulting Publications

• 1.

  2007

  Hemant Varma; Andrew J Skildum; Susan E Conrad

  Functional ablation of pRb activates Cdk2 and causes antiestrogen resistance in human breast cancer cells.

  PloS one 2007;2(12):e1256.

• 2.

  2005

  Shibani Mukherjee; Susan E Conrad

  c-Myc suppresses p21WAF1/CIP1 expression during estrogen signaling and antiestrogen resistance in human breast cancer cells.

  The Journal of biological chemistry 2005;280(18):17617-25.

• 3.

  2004

  Feng Han; Richard Miksicek; Robert Clarke; Susan E Conrad

  Expression of an estrogen receptor variant lacking exon 3 in derivatives of MCF-7 cells with acquired estrogen independence or tamoxifen resistance.

  Journal of molecular endocrinology 2004;32(3):935-45.

• 4.

  2004

  Hua Zhang; Wei Wu; Yan Du; Sarah J Santos; Susan E Conrad; Jack T Watson; Nicholas Grammatikakis; Kathleen A Gallo

  Hsp90/p50cdc37 is required for mixed-lineage kinase (MLK) 3 signaling.

  The Journal of biological chemistry 2004;279(19):19457-63.

• 5.

  2002

  Hemant Varma; Susan E Conrad

  Antiestrogen ICI 182,780 decreases proliferation of insulin-like growth factor I (IGF-I)-treated MCF-7 cells without inhibiting IGF-I signaling.

  Cancer research 2002;62(14):3985-91.

• 6.

  2002

  Andrew J Skildum; Shibani Mukherjee; Susan E Conrad

  The cyclin-dependent kinase inhibitor p21WAF1/Cip1 is an antiestrogen-regulated inhibitor of Cdk4 in human breast cancer cells.

  The Journal of biological chemistry 2002;277(7):5145-52.

• 7.

  2000

  H Varma; S E Conrad

  Reversal of an antiestrogen-mediated cell cycle arrest of MCF-7 cells by viral tumor antigens requires the retinoblastoma protein-binding domain.

  Oncogene 2000;19(41):4746-53.

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