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

Lisa B Frankel, Anne E Lykkesfeldt, Jens B Hansen, Jan Stenvang
Breast Cancer Research and Treatment 2007, 104 (2): 165-79
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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"