Breast cancer cell invasiveness: Correlation with protein kinase C activity and differential regulation by phorbol ester in estrogen receptor-positive and -negative cells

Abstract

Increased protein kinase C (PKC) activity in malignant breast tissue and in most aggressive breast cancer cell lines has suggested a possible role of PKC in breast carcinogenesis and tumor progression. We have investigated here the involvement of PKC in the in vitro invasiveness and motility of several breast cancer cell lines. Modulation of PKC activity by treatment with a phorbol ester (TPA), drastically increased the invasiveness of 2 estrogen receptor‐positive (ER+) lines (MCF7 and ZR 75.1), whereas it markedly decreased the invasiveness of 2 ER− cell lines (MDA‐MB‐231 and MDA‐MB‐435). A PKC inhibitor (H7) reversed the TPA effects in MCF7 cells, whereas it mimicked TPA action in MDA‐MB‐231 cells. All of these effects of TPA also were observed to a similar extent for cell chemotaxis, and they were not dependent on protein neo‐synthesis. In parallel, short TPA treatment induced cell spreading and microtubule organization in MCF7 cells and inverse morphological changes in MDA‐MB‐231 cells. In ER+ cells, constitutive PKC activity and PKCα expression were very low as compared to ER− cells, and this correlated with the invasive potential of the cells. The opposed effects of TPA in ER+ and ER− cells could be due to the abnormal TPA regulation of PKCα observed in ER− cells. Int. J. Cancer 75:750–756, 1998.© 1998 Wiley‐Liss, Inc.

Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion

“…Migrating cells had lower ER levels than non-migrating cells. Finally, treatments such as phorbol ester or pure antiestrogen, known to decrease ER levels in MCF7 breast cancer cells, significantly increased in vitro invasiveness [79,89]. Taken together, these in vitro data indicate a protective role of ER against the invasiveness of breast cancer cells.…”

“…In human breast cancer cell lines, ER expression was associated with low invasiveness and low motility in culture tests [44,79]. Moreover, when ER-positive cells were implanted in nude mice, tumors appeared only in the presence of estrogens and are poorly metastatic as compared to those developed from ER-negative breast cancer cell lines [80].…”

Ets2 and protein kinase Cepsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells

“…Invasive tumour cells often overexpress certain forms of PKCs [36], suggesting that PKCs are involved in tumorigenesis. In support of this notion, PKCα has been found to stimulate invasive behaviour of MCF-7 breast cancer cells [37], whereas PKCε has been shown to inhibit apoptosis of these cells [38].…”

“…This is probably due to a generally anomalous PMA response that correlates with constitutive activation of PKCs, such as PKCα, in these cells [37]. These permanently activated PKCs may also contribute to the regulation of the P3 promoter, as PKC inhibitors reduced TGFβ-induced P3 promoter activity in MDA-MB-231 cells [20].…”

Down-regulation of cathepsin-D expression by antisense gene transfer inhibits tumor growth and experimental lung metastasis of human breast cancer cells

“…In the lower compartment, the DEM medium containing 10% FCS was supplemented with 30 mg/ml fibronectin (Sigma) as chemoattractant. After 24 h at 378C, cells migrating through the filter were evaluated with the mitochondrial deshydrogenase enzymatic assay using 3(4,5-dimethyl-thiazol-2-yl)2,5-diphenol tetrazolium bromide (MTT) and OD 540nm was determined, as previously described (Platet et al, 1998).…”