Protein Kinase D In Breast Cancer Cell Biology Essay

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A protein kinase is an enzyme that phosphorlates other proteins. Phosphorylation usually results in a functional change of the target protein by changing its enzyme activity, cellular location, or association with other proteins [1]. The gene family encoding protein kinases represents the most common human oncogenes. Moreover, mutated and activated protein kinases have been determined to be good targets for the development of new targets for cancer therapies [4]. Evidence has established that several different forms of protein kinase fail to regulate properly in many cancer types, and it has been known that protein kinases play important roles in regulating most cellular functions such as cell growth, apoptosis, DNA damage repair, cell motility, and response to the microenvironment. This research paper will focus on the potential of protein kinase being used as chemotherapeutic targets in cancer treatment such as breast cancer as well as it will highlight recent studies in the development of protein kinase inhibitors in breast cancer cells.

Protein Kinase D in Breast Cancer

Emerging as a major player in cell proliferation, survival, motility, and angiogenesis pathways, it is no surprise that protein kinases has recently received a lot of attention as a potential target in the treatment of many types of cancer such as breast cancer.

Protein kinase D (PKD), the founding member of a new family of serine/threonine protein kinases, occupies a unique position in the signal transduction pathways initiated by DAG and PKC [1]. PKD enzymes were first studied in the context of breast cancer over a decade ago [4]. Despite this early start, the mechanisms through which PKD contributes to breast cancer progression are not yet clear. Analysis of invasive human breast tumors has revealed that protein Kinase D expression is downregulated in infiltrating ductal carcinoma compared to normal breast tissue [5]. Bowden and coworkers [4] studied gene expression using transcriptional microarray of normal breast tissue and of early and advanced-stage breast tumors and shown that there was a reduction of the expression of protein kinase D correlating with increased invasiveness and cancer progression [4].

Functionally, studies investigating the role of protein kinase in breast cancer progression have focused on the processes of invasion and adhesion. As early as 1999, Bowden and colleagues [4] described an interaction between protein kinase, paxillin, and cortactin at sites of invadopodia in breast cancer cells. Invadopodia are actin-containing protrusions that extend outward into the extracellular matrix (ECM) and participate in degradation of the ECM [6]. ECM is a filamentous structure of glycoproteins and proteoglycans that is attached to the cell surface and provides cells with anchorage, traction for movement, and positional recognition [1]. This interaction, present in invasive breast cancer cells but not in non-invasive lines, suggested that protein kinase D may regulate the function or formation of the paxillin/cortactin complex to promote invasion.

Multiple separate studies have strongly supported an opposing role for protein kinase D in breast cancer cell invasion and adhesion. Studies by Eiseler and colleagues [5] have shown that invasion in 2D and 3D environments was reduced with expression of a constitutively active protein kinase D mutant in breast cancer cells. Based on mechanistic argumentation, it has been suggested that the regulation of adhesion and invasion by PKD1 may be related to MMP expression. MMP is an enzyme that degrades matrix proteins. In breast cancer, MMP in particular has been identified as an indicator of potential malignancy [7]. Thus, it is possible that protein kinase D may inhibit breast cancer invasion and metastasis through regulation of MMP expression.

Signaling Mechanism of Protein Kinase D

Emerging evidence links PKD to a diverse set of signal transduction pathways involved in tumor development and cancer progression (Fig. 1). PKD has many potential roles as well as signalling mechanism in cancer-associated responses, such as; proliferations, survival and apoptosis [3].

Uncontrolled cell growth and resistance to apoptosis are among the hallmarks of cancer development. Mechanistically, PKD has been linked to several pathways known to control cell proliferation, most notably the extracellular signal regulated kinase (ERK) signaling pathway [3]. Inhibition of PKD expression and activity has been shown to attenuate ERK signaling, while overexpression of PKD has been shown to potentiate ERK

Fig. 1. PKD has been implicated in the regulation of multiple cancer-promoting pathways. PKC-mediated activation of PKD has been shown to regulate such cellular functions as

proliferation, apoptosis, angiogenesis, migration, and invasion. Dysregulation of these fundamental pathways can lead to the development, progression, and metastasis of cancer.

activity in response to growth factors in multiple cell types including endothelial cells [5].

Studies from Wong and colleagues [3] have described PKD as a potent promoter of cell growth and proliferation in multiple cellular systems, suggesting that PKD may possibly contribute to the cancer phenotype. Cancer is a group of diseases characterized by aberrations in cellular growth, proliferation and survival pathways, resulting in tumor formation and uncontrolled expansion of cancer cells [1]. Kinases such as c-Src, c-Abl, mitogen activated protein (MAP) kinase, phosphotidylinositol-3-kinase (PI3K) AKT, and the epidermal growth factor (EGF) receptor are commonly activated in cancer cells, and are known to contribute to tumorigenesis. Many of these occur in the same signalling pathway [2]. Research groups have developed several ways to target these enzymes therapeutically, such as with antibodies or small molecules that block kinase-substrate interaction, or that inhibit the enzyme's adenosine triphosphate (ATP) binding site. A number of kinase inhibitors have therefore already been developed and approved for cancer treatment. The potential for targeting kinases in the treatment of cancer was the theme of the Keystone Symposium "Protein Kinases and Cancer: The Promise of Molecular Based Therapies" recently held in Tahoe City, California [2]. In the opening address, Robert Wittes [2], of the Memorial Sloan-Kettering Cancer Center, NY, discussed the pros and cons of targeting kinases in cancer patients. One of the main pros was that kinase inhibitors designed to block the enzyme's ATP binding site can have broad specificity such as that with imatinib that not only inhibits the tyrosine kinase c-Abl, but also c-Kit and the platelet-derived growth factor (PDGF) receptor tyrosine kinases. So it can be used to treat many types of tumors associated with activation of these signalling molecules [2].

Protein Kinase D as a chemotherapeutic target

Immunohistochemistry analysis of multiple types of human malignant lymphoma have revealed varying expression of protein kinase and activity [8]. T. Eiseler and colleagues suggest in their research experiment that protein kinase expression often were very similar to the normal lymph tissue from which the particular tumors were derived. This study suggests that while protein kinase is expressed in many types of lymphoma, it may not be involved in progression of the disease; however, more studies are required to support these conclusions [5].


In conclusion extensive evidence indicates that protein kinase expression is deregulated in multiple cancer types and plays an active role in a variety of cancer-associated biological processes including proliferation, survival, apoptosis, migration, invasion, and angiogenesis, making protein kinase an attractive target for drug development [3]. To date, there have been no reports of genetic protein kinase animal models related to breast cancer. However, despite this, pharmacological inhibition of protein kinase has now shown to be effective at suppressing growth of pancreatic tumor xenografts [15], which greatly enhances the validity of protein kinase as a chemotherapeutic target.

Literature Cited:

[1], Definitions for biochemical terms, accessed Nov. 8th, 2010.

[2] S. Fogarty, D.G. Hardie, Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer, Biochimica et Biophysica Acta (BBA) - Proteins & Proteomics, Volume 1804, Issue 3, March 2010, Pages 581-591

[3] C. Wong, Z.G. Jin, Protein kinase C-dependent protein kinase D activation modulates ERK signal pathway and endothelial cell proliferation by vascular endothelial growth factor, J. Biol. Chem. 280 (2005) 33262-33269

[4] E.T. Bowden, M. Barth, D. Thomas, R.I. Glazer and S.C. Mueller, An invasion-related complex of cortactin, paxillin and PKCmu associates with invadopodia at sites of extracellular matrix degradation, Oncogene 18 (1999), pp. 4440-4449.

[5] T. Eiseler, H. Doppler, I.K. Yan, S. Goodison and P. Storz, Protein kinase D1 regulates matrix metalloproteinase expression and inhibits breast cancer cell invasion, Breast Cancer Res. 11 (2009), p. R13.

[6] S.S. Stylli, A.H. Kaye and P. Lock, Invadopodia: at the cutting edge of tumour invasion, J. Clin. Neurosci. 15 (2008), pp. 725-737.

[7] A. Jezierska and T. Motyl, Matrix metalloproteinase-2 involvement in breast cancer progression: a mini-review, Med. Sci. Monit. 15 (2009), pp. RA32-RA40.

[8] K.B. Harikumar, A.B. Kunnumakkara, N. Ochi, Z. Tong, A. Deorukhkar, B. Sung, L. Kelland, S. Jamieson, R. Sutherland, T. Raynham, M. Charles, A. Bagherazadeh, C. Foxton, A. Boakes, M. Farooq, D. Maru, P. Diagaradjane, Y. Matsuo, J. Sinnett-Smith, J. Gelovani, S. Krishnan, B.B. Aggarwal, E. Rozengurt, C.R. Ireson and S. Guha, A novel small-molecule inhibitor of protein kinase D blocks pancreatic cancer growth in vitro and in vivo, Mol. Cancer Ther. 9 (2010), pp. 1136-1146.

[9]   Sushovan Guha, Suebpong Tanasanvimon, James Sinnett-Smith, Enrique Rozengurt, Role of protein kinase D signaling in pancreatic cancer, Biochemical Pharmacology (2010).