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Session III : Protein kinase cascades as therapeutic targets Poster III, 33
Protein kinase C-eta as a possible therapeutic target in breast cancer
Etta Livneh, Galia Oberkobitz, Noa Rotem, Galia Karp, Adva Maissel and Galit Shahaf.
Department of Microbiology and Immunology, Ben Gurion University, Beer Sheva
84105, Israel, e-mail:etta@bgumail.bgu.ac.il
Protein kinase C (PKC) is involved in several major signal transduction pathways that control
gene expression, cell growth and differentiation. However, these kinases were not thoroughly
explored for their chemotherapeutic values. Here we have explored PKCeta as a possible
target for chemotherapy in breast cancer. PKCeta was recently suggested as a therapeutic
target in glioblastoma multiforme. PKCeta, expressed primarily in epithelial cells, appears as
a candidate regulator of mammary gland proliferation or differentiation, as its expression is
specifically up-regulated in the mammary gland during the transit from resting to pregnant
state. This prompt us to examine the hormonal regulation of its expression by estrogen and
progesterone as their levels are also up-regulated during pregnancy. We show that estradiol
gradually increased the expression of PKCeta in the estrogen-responsive lines MCF-7 and
T47D, but not in the estrogen non-responsive line MDA-MB 231. In contrast to the observed
up-regulation of PKCeta, the PKCdelta isoform was down-regulated while PKCalpha
expression was unaltered, demonstrating different response to estradiol stimulation.
Moreover, the presence of progesterone, involved in the differentiation of the mammary
gland, reduced the estrogen- induced PLCeta expression in a time-dependent manner.
Interestingly, our recent studies suggest also a role in apoptosis for PKCeta. Here we have
investigated its role in cell death induced by the DNA damaging agents UV irradiation and
the anti-cancer drug– Camptothecin (CPT). Our studies showed that the inducible expression
of PKCeta in MCF-7 cells provided partial resistance against cell death, which was
accompanied by increased cell survival and PARP cleavage. Furthermore, we show that JNK
activity required for apoptosis in MCF-7 cells was inhibited by the inducible expression of
PKCeta. Thus, our studies suggest that PKCeta has an important role in the hormonal
regulation, cell cycle control and resistance to DNA damage in breast cancer cells. These
properties could make PKCeta a target for chemotherapeutic intervention in breast cancer.
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