Diacylglycerol Signaling

17 PKC and Breast Cancer
The array of changes in isozyme expression upon transfection with PKCa once
again makes it difficult to assign a direct role to PKCa in regulating cell proliferation.
Broad effects such as this do, however, open the door for future research into
the role of cross talk between isozymes (Ventura et al. 2009). Furthering the support
of cross talk between PKCa and b, small hairpin RNA (shRNA) knockdown of
PKCa in T47D breast cancer cells results in reduced PKCb levels (Lin et al. 2006).
Of note, however, the reciprocal experiment results in upregulation of both PKCb
and d (Tonetti et al. 2000). Once again, context is crucial when analyzing the effects
and expression of PKC isozymes, as both characteristics vary between cell lines (as
shown above) and between in vitro and in vivo settings (Lin et al. 2006).
Both PKCd and h are involved in cell cycle regulation through influencing the
G 1 /S phase transition. Both isozymes exert their regulatory effects through the
cyclin E/Cdk2 complex. PKCd mediates G 1 arrest through a p21-dependent pathway
in SKBR-3 breast cancer cells and a p27 Kip1 -dependent pathway in MCF-7
(Yokoyama et al. 2005; Shanmugam et al. 2001; Vucenik et al. 2005). Both p21 and
p27 Kip1 can bind to the cyclin E/Cdk2 complex, and thereby inhibit its activity. In
contrast, PKCh directly associates with the cyclin E/Cdk2 complex, leading to G 1
arrest in MCF-7 and NIH-3T3 cells (Shtutman et al. 2003). PKCd can also mediate
G 1 arrest through a phosphorylated retinoblastoma protein (pRb)-dependent mechanism
in MCF-7 cells (Vucenik et al. 2005). Because of these tumor suppressive
effects, it is not surprising that PKC d is downregulated in the previously referenced
more aggressive PKCa-transfected MCF-7 cells, and that PKCh is downregulated
in invasive breast cancer (Masso-Welch et al. 2001). In order to fully comprehend
the role of PKC in tumorigenesis, it will be required that cell cycle regulation be
temporally integrated into their dynamic modulation of signal transduction.
17.6 Metastasis
Primary tumors constitute severe disease in their own right, but the vast majority of
cancer-related deaths are due to metastatic spread to vital organs. Metastasis is a
complex process involving extensive interaction with, and remodeling of, the tumor
microenvironment by invading cancer cells, and subsequent colonization of a new
microenvironment – most notably lungs, bone, brain, pleura, and liver in breast
cancer (Saenz and Phillips 1998). With the array of processes required of cancer
cells in order to metastasize – motility, invasion, and (lymph)angiogenesis, to name
a few – it is not surprising that PKC, one of the major intracellular signaling hubs,
plays a broad and important role.
In order for cancer cells to invade both locally and into secondary sites, they
need to be able to move. PKCd has been shown to suppress migration in MCF-7
cells (Jackson et al. 2005). This downregulation may be due in part to regulation by
PKCa. As previously described, MCF-7 cells transfected with PKCa showed
decreased levels of PKCd. Injecting these cells into nude mice resulted in an
increased number of metastases compared to vector controls (Ways et al. 1995),
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