Gene expression response to the protein kinase C (PKC) activator PMA (TPA) is much higher in luminal epithelial-like (MCF-7) than in fibroblast-like (MDA-MB-231) breast cancer cells.

scimedweb scimedweb at
Fri Oct 15 02:52:18 EST 2004

Gene regulation by phorbol 12-myristate 13-acetate (PMA) in MCF-7 and
MDA-MB-231, two breast cancer cell lines exhibiting highly different
by Marc Lacroix et al., Institut Jules Bordet Institute, Bruxelles
(Brussels), Belgique (Belgium)
in Oncology Reports (2004) 12, 701-707

We have examined the effects of the protein kinase C (PKC)-activator
phorbol 12-myristate 13-acetate (PMA) on gene expression in two breast
cancer cell (BCC) lines exhibiting highly different phenotypes. These
are the estrogen receptor alpha (ERalpha)-positive, weakly invasive,
luminal epithelial-like MCF-7 and the ERalpha-negative, highly
invasive, fibroblast-like MDA-MB-231. They express constitutively low
and high PKC activities, respectively. After a 24-h exposition to 100
nM PMA, the number of genes showing an altered expression at the
2-fold change level was much higher in MCF-7 (n=435) than in
MDA-MB-231 (n=18) BCC. Four of these genes, namely CDC2 (Cell division
cycle 2), CENPA (Centromere protein A (17 kDa)), NR4A1 (Nuclear
receptor subfamily 4, group A, member 1), and MMP10 (Matrix
metalloproteinase 10 (stromelysin 2)), were altered in the same way in
both cell lines. Two genes were regulated in an opposite way: ID1
(Inhibitor of DNA binding 1, dominant negative helix-loop-helix
protein) and EVA1 (Epithelial V-like antigen 1). Many of the genes
down-regulated in MCF-7 BCC appeared to be preferentially expressed in
G1, S and/or G2 phases of the cell cycle. The ERalpha gene, ESR1, and
other genes associated to the ERalpha-positive, luminal
epithelial-like BCC phenotype were down-regulated, while a series of
genes related to a more aggressive, fibroblast-like phenotype were
up-regulated. Other altered genes were notably linked to cell
architecture, supporting profound effects of PMA on cell morphology
and motility, as well as on the interactions between BCC and the
neighboring proteins. Of note, all the modulated genes involved in
proteolysis and its control were up-regulated. In summary, PMA effects
suggest that PKC activation may induce, to some extent, a more
fibroblast-like phenotype in the ERalpha-positive, luminal
epithelial-like MCF-7 BCC, and significantly modulate the interactions
of these cells with their environment.

Genes most up- or down-regulated in MCF-7 BCC:

MMP1 (Matrix metalloproteinase 1 (interstitial collagenase)), PRKACA
(Protein kinase, cAMP-dependent, catalytic, alpha), PLAB (Prostate
differentiation factor), S100A9 (S100 calcium binding protein A9
(calgranulin B)), S100P (S100 calcium binding protein P), SERPINA3
(Serine (or cysteine) proteinase inhibitor, clade A, member 3), AKR1C4
(Aldo-keto reductase family 1, member C4), KRTHB1 (Keratin, hair,
basic, 1), MMP10 (Matrix metalloproteinase 10 (stromelysin 2)), BIRC3
(Baculoviral IAP repeat-containing 3), CDKN1A (Cyclin-dependent kinase
inhibitor 1A (p21, Cip1)), GLRX (Glutaredoxin (thioltransferase)),
ORM1 (Orosomucoid 1), AKR1C1 (Aldo-keto reductase family 1, member C1
(dihydrodiol dehydrogenase 1)), KCNF1 (Potassium voltage-gated
channel, subfamily F, member 1), H11 (Protein kinase H11), LTB
(Lymphotoxin beta (TNF superfamily member 3)), RAI3 (Retinoic acid
induced 3), KRTHB3 (Keratin, hair, basic, 3), ELL2 (Elongation factor,
RNA polymerase II, 2), DGAT2 (Diacylglycerol O-acyltransferase homolog
2 (mouse)), MMP9 (Matrix metalloproteinase 9)

TRGV9 (T-cell receptor gamma locus), IGFBP5 (Insulin-like growth
factor binding protein 5), EXO1 (Exonuclease 1), SKP2 (S-phase
kinase-associated protein 2 (p45)), ADD3 (Adducin 3, gamma), NR2F2
(Nuclear receptor subfamily 2, group F, member 2), PCNA (Proliferating
cell nuclear antigen), MYB (v-myb myeloblastosis viral oncogene
homolog (avian)), TXNIP (Thioredoxin interacting protein), BBOX1
(Butyrobetaine (gamma), 2-oxoglutarate dioxygenase 1), SSFA2 (Sperm
specific antigen 2), EPLIN (Epithelial protein lost in neoplasm beta),
CCNE2 (Cyclin E2), BCHE (Butyrylcholiesterase), RFC4 (Replication
factor C (activator 1), 4), TYMS (Thymidylate synthetase), VAV3 (vav3
oncogene), MCM2 (MCM2 minichromosome maintenance deficient 2, mitotin
(S. cerevisiae))

Genes up- or down-regulated in MDA-MB-231 BCC:

SERPINB2 (Serine (or cysteine) proteinase inhibitor, clade B
(ovalbumin), member 2), PTGS2 (Prostaglandin-endoperoxidase synthase 2
(cyclooxygenase 2), TFPI2 (Tissue factor pathway 2), MMP10 (Matrix
metalloproteinase 10 (stromelysin 2)), IL1B (Interleukin 1 beta),
SGNE1 (Secretory granule, neuroendocrine protein 1 (7B2 protein)),
PPARD (Peroxisome proliferative activated receptor delta), NR4A1
(Nuclear receptor subfamily 4, group A, member 1), MMP3 (Matrix
metalloproteinase 3 (stromelysin 1))

ID1 (Inhibitor of DNA binding 1, dominant negative helix-loop-helix
protein), SNCA (Synuclein alpha (non A4 component of amyloid
precursor)), CCNA1 (Cyclin A1), SERPINA5 (Serine (or cysteine)
proteinase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin),
member 5), PFN2 (profilin 2), EVA1 (Epithelial V-like antigen 1),
CENPA (Centromere protein A (17 kDa)), CDC2 (Cell division cycle 2),
HEPH (Hephaestin)

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