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

TY - JOUR

T1 - Protein Kinase C alpha is a marker for antiestrogen resistance and is involved in the growth of tamoxifen resistant human breast cancer cells.

AU - Frankel, Lisa

AU - Lykkesfeldt, Anne E

AU - Hansen, Jens B

AU - Stenvang, Jan

N1 - Keywords: Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Estrogen Antagonists; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoprecipitation; Oligonucleotides; Protein Kinase C-alpha; Tamoxifen; Tumor Markers, Biological

PY - 2006

Y1 - 2006

N2 - 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 alpha (PKCalpha) 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 PKCalpha contributes to antiestrogen resistant growth. A panel of nine resistant cell lines was investigated, all of which displayed elevated levels of PKCalpha expression relative to parental MCF-7 cells. Stable PKCalpha 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/TAM(R)-1 (TAM(R)-1) and ICI 182,780 resistant MCF-7/182(R)-6 (182(R)-6). Treatment with the PKCalpha 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 PKCalpha resulted in a 30-40% growth inhibition of TAM(R)-1 and 182(R)-6, while MCF-7 remained unaffected. Stable PKCalpha knock-down in TAM(R)-1 using small hairpin RNA, resulted in a tamoxifen sensitive "MCF-7-like" growth phenotype, while the same approach in 182(R)-6 cells did not alter their sensitivity to ICI 182,780. These results demonstrate a functional contribution of PKCalpha to tamoxifen resistant growth. Furthermore, our data suggest the potential for PKCalpha as a marker for antiestrogen resistance and as a promising therapeutic target in the treatment of tamoxifen resistant breast cancer.

AB - 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 alpha (PKCalpha) 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 PKCalpha contributes to antiestrogen resistant growth. A panel of nine resistant cell lines was investigated, all of which displayed elevated levels of PKCalpha expression relative to parental MCF-7 cells. Stable PKCalpha 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/TAM(R)-1 (TAM(R)-1) and ICI 182,780 resistant MCF-7/182(R)-6 (182(R)-6). Treatment with the PKCalpha 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 PKCalpha resulted in a 30-40% growth inhibition of TAM(R)-1 and 182(R)-6, while MCF-7 remained unaffected. Stable PKCalpha knock-down in TAM(R)-1 using small hairpin RNA, resulted in a tamoxifen sensitive "MCF-7-like" growth phenotype, while the same approach in 182(R)-6 cells did not alter their sensitivity to ICI 182,780. These results demonstrate a functional contribution of PKCalpha to tamoxifen resistant growth. Furthermore, our data suggest the potential for PKCalpha as a marker for antiestrogen resistance and as a promising therapeutic target in the treatment of tamoxifen resistant breast cancer.

U2 - 10.1007/s10549-006-9399-1

DO - 10.1007/s10549-006-9399-1

M3 - Journal article

C2 - 17061041

SN - 0167-6806

VL - 104

SP - 165

EP - 179

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 2

ER -