Elevation of protein kinase A and protein kinase C activities in malignant as compared with normal human breast tissue

Gordge, Philip C.; Hulme, M. J.; Clegg, Roger A.; Miller, William R.

doi:10.1016/s0959-8049(96)00255-9

Cited by 108 publications

(74 citation statements)

References 18 publications

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“…PKC levels are higher in breast cancer specimens than in normal breast tissue 60 and it has been suggested that PKC may mediate the effect of local growth factors in stimulating progression in premalignant cells. 61 It is reported that PKC activity in human breast cancer cell lines is increased by estradiol and inhibited by the anti-estrogen tamoxifen.…”

Section: Endocrine±metabolic Markers Of High Riskmentioning

confidence: 99%

Adiposity as a risk determinant for postmenopausal breast cancer

2000

Int J Obes

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BACKGROUND: Cross-cultural studies have long suggested that the high incidence of breast cancer in developed Western countries may be linked to the high prevalence of obesity and to high total energy intake. Recent studies show that hyperinsulinemia, increased concentration of insulin-like growth factor 1 and greater abdominal fat accumulation are markers of high risk for breast cancer. Increased serum concentrations of free estradiol and free testosterone are similar risk markers and are frequent concomitants of hyperinsulinemia. MECHANISMS: The mechanism by which such metabolic ± endocrine abnormality may promote mammary carcinogenesis is uncertain, but its effect is likely to predominate in the years approaching the menopause when obesity is common among Western women. In obese subjects, enlargement of adipose deposits is known to produce an excess of free fatty acids and tumor necrosis factor alpha, both of which may be involved in the pathogenesis of insulin resistance. In middle-aged women, the concomitants of hyperinsulinemia may activate invasive and proliferative activity in preneoplastic mammary lesions such as in situ duct carcinoma of the comedo type. This will enhance the risk of progression to invasive breast cancer, which is likely to manifest clinically mainly after the menopause. CONCLUSION: Weight reduction combined with a program of regular physical exercise has been shown to reduce both estrogen and insulin concentrations in obese women and such a regimen might be tested in clinical trials for an effect on breast cancer risk in obese women. Intervention is best begun around the age of 45 y, this being the age when in situ duct carcinoma would normally begin to show evidence of spontaneous involution in women without clinical evidence of invasive breast cancer.

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Section: Endocrine±metabolic Markers Of High Riskmentioning

confidence: 99%

Adiposity as a risk determinant for postmenopausal breast cancer

2000

Int J Obes

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“…These results implicate alterations in PKC function in the progression of mammary cells to a transformed state. Increased Ca 2+ -dependent PKC activity, and PKCa protein levels, were found when primary breast tumors were compared to normal adjacent tissue (Gordge et al, 1996;O'Brian et al, 1989). Amongst breast cancers an increase in total PKC activity has been associated with the more biologically aggressive estrogen-receptor negative and EGF-receptor positive subset (Borner et al, 1987;Fabbro et al, 1986Fabbro et al, , 1992.…”

Section: Introductionmentioning

confidence: 99%

“…The phenotypic e ects of ectopic overexpression of speci®c isoforms of PKC in various cell types are strongly dependent on both the cell type and isoform examined (Blumberg et al, 1994;Borner et al, 1991;Cacace et al, 1993;Housey et al, 1988). Several studies implicate an important role for PKC in human breast cancers Gordge et al, 1996;Kiley et al, 1996;O'Brian et al, 1989). Treatment of normal mammary epithelial cells with phorbol esters stimulated proliferation, whereas phorbol esters inhibited the growth of breast cancer cell lines (Kiley et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

The α isoform of protein kinase C mediates phorbol ester-induced growth inhibition and p21cip1 induction in HC11 mammary epithelial cells

et al. 1999

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“…Situated at the crossroads of many signal transduction pathways, PKCs are activated by upstream signaling elements such as growth factor receptors (for example, platelet-derived growth factor receptor), and are able to activate downstream signaling molecules such as the proto-oncogene Raf-1 (Schenk and Snaar-Jagalska, 1999;Liebmann, 2001). In fact, PKC activity is increased in some human tumors compared with their normal counterpart (O'Brian et al, 1989;Alvaro et al, 1992;Gordge et al, 1996). Furthermore, a large variety of structurally and mechanistically distinct PKC inhibitors were reported to have potent antitumor activity in vitro and in vivo (Goekjian and Jirousek, 2001;Swannie and Kaye, 2002;da Rocha et al, 2002).…”

mentioning

confidence: 99%

Activation of protein kinase C promotes human cancer cell growth through downregulation of p18INK4c

et al. 2004

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p18 INK4c , a member of INK4 family of cyclin-dependent kinase inhibitors, negatively regulates the cyclin D-cyclindependent kinase 4/6 complexes which promote G1/S transition by phosphorylating the retinoblastoma tumorsuppressor gene product. Several recent studies using p18 INK4c -null mice revealed that the p18 INK4c plays an important role in cell proliferation and tumor development. We report here that 12-O-tetradecanoylphorbol-13-acetate (TPA), widely used as a protein kinase C (PKC) activator, suppresses the expression of p18 INK4c through its promoter, accompanied by the induction of human cancer cell growth. Reduction of p18 INK4c using small interfering RNA (siRNA) also enhanced cell growth, suggesting that p18 INK4c is a critical target of TPA. Ro 31-8425, a potent and highly specific PKC inhibitor abrogated the suppressive effect of TPA on p18 INK4c gene expression. However, the expression of dominant-negative c-Jun (TAM-67) did not inhibit the action of TPA on p18 INK4c . These findings suggest that activation of PKC promotes human cancer cell growth through downregulation of p18 INK4c in an AP-1 activation-independent manner. These results suggest that the accelerated cellular proliferation of some human tumors caused by enhanced PKC activity at least partially involves the suppression of p18 INK4c , which is a ubiquitously expressed cyclin-dependent kinase inhibitor.

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Elevation of protein kinase A and protein kinase C activities in malignant as compared with normal human breast tissue

Cited by 108 publications

References 18 publications

Adiposity as a risk determinant for postmenopausal breast cancer

Adiposity as a risk determinant for postmenopausal breast cancer

The α isoform of protein kinase C mediates phorbol ester-induced growth inhibition and p21cip1 induction in HC11 mammary epithelial cells

Activation of protein kinase C promotes human cancer cell growth through downregulation of p18INK4c

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