p27(Kip1) is deregulated in tamoxifen resistant breast cancers through activation of receptor tyrosine kinases and cSrc kinases .
Published: 2006
Language: eng
Number of pages: 131
ISBN-13: 9780494219195
Description: Here I show that the dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), can restore tamoxifen sensitivity in the ER positive cell lines: MCF-7 pr, T-47D and ZR-75. Restoration of tamoxifen response is associated with reduction of cyclin D1, increase of p27 and p27 associated with cyclin E-Cdk2 that is greater when the two drugs, lapatimb and tamoxifen, are used in combination, than with either alone. Lapatinib in combination with tamoxifen also effectively inhibited tamoxifen resistant MCF-7 xenografts.Similarly inhibition of cSrc with the cSrc/Abl specific inhibitor AZD0530 also restored tamoxifen sensitivity in a cSrc overexpressing, tamoxifen resistant cell line. I present evidence that cSrc phosphorylates p27 at tyrosine 74 and tyrosine 88 in vitro and in vivo. cSrc phosphorylated p27 shows reduced cyclin E-Cdk2 inhibition. cSrc transfection reduced cyclin E-Cdk2 bound p27. cSrc activated breast cancer lines show increased p27-cSrc complexes and cSrc siRNA and cSrc inhibitors increase cellular p27. cSrc activation upon mitogen stimulation coincides with increased cSrc-p27 co-precipitation in early G1 and precedes the loss of cyclin E-Cdk2 from p27. These data provide a strong rationale for further investigation of the therapeutic potential of cSrc and ErbB1/ErbB2 inhibitors combined with antiestrogens in the treatment of ER positive breast cancers.The estrogen receptor-blocking drug, tamoxifen is used for breast cancer to block the mitogenic effect of estrogen on breast cancer cells. Tamoxifen treatment activates the cyclin dependent kinase inhibitor, p27kip1  to mediate G1 arrest. However, initially responsive tumors invariably acquire resistance to treatment. This is often associated with increased expression of the epidermal growth factor receptor family members, ErbB1 and ErbB2. cSrc is activated by receptor tyrosine kinases and by cross talk with liganded estrogen receptor. Work of this thesis has shown that ErbB1, ErbB2 or cSrc overexpression can abrogate tamoxifen sensitivity in breast cancer lines through both reduction of p27 levels and inhibition of its function.
Notes: Source: Dissertation Abstracts International, Volume: 68-01, Section: B, page: 0084.

Thesis (Ph.D.)--University of Toronto, 2006.

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