MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype.

Ways, D. Kirk; Kukoly, Cindy; DeVente, James; Hooker, Jerry; Bryant, W O; Posekany, Karla J.; Fletcher, Donald J.; Cook, Paul P.; Parker, Peter J.

doi:10.1172/jci117872

Cited by 254 publications

(201 citation statements)

References 31 publications

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“…The a-isozyme of PKC, PKCa, is widely expressed in various tissues, and PKCa expression and activity have been found to be higher in some types of tumors than in normal tissues (Lahn et al, 2004;Michie and Nakagawa, 2005). Breast cancer cells engineered to express exogenous PKCa protein have been found to display a more aggressive phenotype (Ways et al, 1995). In addition to the role PKCa plays in cell transformation and tumorigenesis, studies have indicated that elevated PKCa activity in some human carcinoma cells, including breast cancer cells, is associated with an increased invasive or metastatic potential (Morse-Gaudio et al, 1998;Masur et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

Tan

Sun

et al. 2006

Oncogene

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Although ErbB2 is known to enhance breast cancer metastasis, the signaling events responsible for this remain elusive. a-Isozyme of protein kinase C (PKCa), which is involved in cancer development and progression, has been suggested to be activated by ErbB2 without direct evidence. In addition, the roles of PKCa in ErbB2-mediated cancer cell malignancy have not been clearly identified. In this study, we investigated whether ErbB2 can activate PKCa and determined what role PKCa plays in ErbB2-mediated breast cancer cell invasion. We expressed wild-type and mutant ErbB2 with altered signaling capacities in MDA-MB-435 breast cancer cells and revealed that overexpression or activation of ErbB2 in MDA-MB-435 cells upregulated and activated PKCa and that downregulation of ErbB2 by small-interfering RNA decreased the expression and activity of PKCa in BT474 breast cancer cells. These in vitro results were supported by data from breast cancer patient samples. In 150 breast cancer tumor samples, ErbB2-overexpressing tumors showed significantly higher positive rates of PKCa membrane immunohistochemistry staining than that of ErbB2-low-expressing tumors. Mechanistically, we found that PKCa is co-immunoprecipitated with Src and PKCa expression and activity can be decreased by Src inhibitor PP2 and by the expression of a dominantnegative mutant of Src. Moreover, ErbB2-mediated upregulation of urokinase-type plasminogen activator receptor (uPAR) is reduced by either the PKCa inhibitor Go6976 or the Src inhibitor PP2, and the combination of Go6976 with PP2 is superior to either agent alone in suppressing uPAR expression and cell invasion. These results demonstrate that PKCa is critical for ErbB2-mediated cancer cell invasion and provide valuable insights for current and future PKCa and Src inhibitor clinical trials.

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Section: Introductionmentioning

confidence: 99%

Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

Tan

Sun

et al. 2006

Oncogene

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“…PKC activity is involved in integrin-mediated responses including adhesion, motility and membrane ru ing (Lewis et al, 1996;Klemke et al, 1994;Yebra et al, 1995;Miyata et al, 1989). It can also a ect invasive behavior (Ways et al, 1995). PKC activation has been demonstrated as a controlling factor in the reabsorbtion activity exhibited by osteoclasts, a non-transformed cell type, responsible for bone remodeling (Moonga et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

An invasion-related complex of cortactin, paxillin and PKCμ associates with invadopodia at sites of extracellular matrix degradation

et al. 1999

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Invasive breast cancer cells have the ability to extend membrane protrusions, invadopodia, into the extracellular matrix (ECM). These structures are associated with sites of active matrix degradation. The amount of matrix degradation associated with the activity of these membrane protrusions has been shown to directly correlate with invasive potential. We demonstrate here that microinjection of polyclonal anti-cortactin antibodies blocks matrix degradation at invadopodia supporting the hypothesis that cortactin has a direct role in invasive behavior. MDA-MB-231, invasive breast cancer cells were sheared from the surface of a gelatin matrix to isolate invadopodia. Cortactin, paxillin and protein kinase C (PKC) m, a serine kinase, were co-immunoprecipitated as a complex from invadopodia-enriched membranes. We con®rmed the subcellular distribution of these proteins by immunolocalization and Western blotting. We also determined that, in contrast to its presence in invasive cells, this complex of proteins was not detected in lysates from non-invasive cells that do not form invadopodia. Taken together, these data suggest that the formation of this cortactin-containing complex correlates with cellular invasiveness. We hypothesize that this complex of molecules has a role in the formation and function of invadopodia during cellular invasion.

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“…For example, overexpressing PKCe in normal ®broblasts increased anchorage-dependent and -independent growth, whereas overexpressing PKCa and d inhibited growth (Cacace et al, 1993;Mischak et al, 1993;Watanabe et al, 1992;Yamaguchi et al, 1995). In contrast, overexpressing PKCa in MCF7 mammary tumor cells increased anchorage-dependent and independent growth (Ways et al, 1995). The fact that overexpressing an individual isozyme causes di erent growth responses depending on the cell type indicates that the relationship between individual PKCs and carcinogenesis is complicated and cannot be generalized.…”

Section: Introductionmentioning

confidence: 99%

“…While there is some evidence that increased PKC activity may be important in mammary carcinogenesis (Ways et al, 1995), there is little information on the role of individual PKCs in this process. To investigate the involvement of individual PKCs in mammary tumor (MT) promotion/progression, we compared PKC isozyme levels in MT cell lines that di er in growth rate and metastatic potential.…”

Section: Introductionmentioning

confidence: 99%

Increased protein kinase Cδ in mammary tumor cells: relationship to transformation and metastatic progression

et al. 1999

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Relatively little is known about the molecular mechanisms of tumor promotion/progression in mammary carcinogenesis. Increased protein kinase C (PKC) activity is known to promote tumor formation in several tissues; however, its role in mammary carcinogenesis is not yet known. To determine if individual PKCs may selectively regulate properties of mammary tumor cells, we compared PKC isozyme levels in mammary tumor cell lines with low, moderate and high metastatic potential. All three cell lines expressed a, d, e and z PKCs; however, PKCd levels were relatively increased in the highly metastatic cells. To determine if increased PKCd could contribute to promotion/progression, we overexpressed PKCd in the low and moderately metastatic cell lines. PKCd overexpression had no signi®cant e ect on growth of adherent cells, but signi®cantly increased anchorage-independent growth. Conversely, expressing the regulatory domain of PKCd (RDd), a putative PKCd inhibitory fragment, inhibited anchorage-independent growth. The e cacy of RDd as a PKCd inhibitor was demonstrated by showing that RDd selectively interfered with PKCd subcellular location and signi®cantly interfered with phosphorylation of the PKC cytoskeletal substrate, adducin. PKC-dependent phosphorylation of cytoskeletal substrate proteins, such as adducin, provides a mechanistic link between increased PKCd activity and phenotypic changes in cytoskeletaldependent processes such as migration and attachment, two processes that are relevant to metastatic potential. The reciprocal growth e ects of expressing PKCd and RDd as gain and loss of function constructs, respectively, provide strong evidence that PKCd regulates processes important for anchorage-independent growth in these mammary tumor cells.

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MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype.

Cited by 254 publications

References 31 publications

Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

Upregulation and activation of PKCα by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKCα and Src inhibitors

An invasion-related complex of cortactin, paxillin and PKCμ associates with invadopodia at sites of extracellular matrix degradation

Increased protein kinase Cδ in mammary tumor cells: relationship to transformation and metastatic progression

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