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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 2/2007

01-08-2007 | Original Paper

Protein Kinase C α is a marker for antiestrogen resistance and is involved in the growth of tamoxifen resistant human breast cancer cells

Authors: Lisa B. Frankel, Anne E. Lykkesfeldt, Jens B. Hansen, Jan Stenvang

Published in: Breast Cancer Research and Treatment | Issue 2/2007

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Abstract

Development of resistance to antiestrogen treatment in breast cancer patients is a serious therapeutic problem. The molecular mechanisms contributing to resistance are currently unclear; however it is known that increased activation of growth signaling pathways is involved. Protein Kinase C α (PKCα) is associated with a diverse range of cancers and is previously shown to be overexpressed in three out of four antiestrogen resistant breast cancer cell lines. In this study we investigated whether PKCα contributes to antiestrogen resistant growth. A panel of nine resistant cell lines was investigated, all of which displayed elevated levels of PKCα expression relative to parental MCF-7 cells. Stable PKCα overexpression in MCF-7 cells significantly reduced sensitivity to the antiestrogens, tamoxifen and ICI 182,780. Two resistant cell lines were chosen for further studies: tamoxifen resistant MCF-7/TAMR-1 (TAMR-1) and ICI 182,780 resistant MCF-7/182R-6 (182R-6). Treatment with the PKCα inhibitor Ro-32–0432 resulted in a preferential growth inhibition of these two cell lines relative to MCF-7 cells. Moreover, transient down-regulation of PKCα resulted in a 30–40% growth inhibition of TAMR-1 and 182R-6, while MCF-7 remained unaffected. Stable PKCα knock-down in TAMR-1 using small hairpin RNA, resulted in a tamoxifen sensitive “MCF-7–like” growth phenotype, while the same approach in 182R-6 cells did not alter their sensitivity to ICI 182,780. These results demonstrate a functional contribution of PKCα to tamoxifen resistant growth. Furthermore, our data suggest the potential for PKCα as a marker for antiestrogen resistance and as a promising therapeutic target in the treatment of tamoxifen resistant breast cancer.
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Metadata
Title
Protein Kinase C α is a marker for antiestrogen resistance and is involved in the growth of tamoxifen resistant human breast cancer cells
Authors
Lisa B. Frankel
Anne E. Lykkesfeldt
Jens B. Hansen
Jan Stenvang
Publication date
01-08-2007
Published in
Breast Cancer Research and Treatment / Issue 2/2007
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-006-9399-1

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