The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-γ1 signalling in breast cancer cell migration and dissemination
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The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-γ1 signalling in breast cancer cell migration and dissemination. / Balz, Lydia M; Bartkowiak, Kai; Andreas, Antje; Pantel, Klaus; Niggemann, Bernd; Zänker, Kurt S; Brandt, Burkhard; Dittmar, Thomas.
In: J PATHOL, Vol. 227, No. 2, 2, 06.2012, p. 234-244.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The interplay of HER2/HER3/PI3K and EGFR/HER2/PLC-γ1 signalling in breast cancer cell migration and dissemination
AU - Balz, Lydia M
AU - Bartkowiak, Kai
AU - Andreas, Antje
AU - Pantel, Klaus
AU - Niggemann, Bernd
AU - Zänker, Kurt S
AU - Brandt, Burkhard
AU - Dittmar, Thomas
N1 - Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
PY - 2012/6
Y1 - 2012/6
N2 - HER2 signalling by heterodimerisation with EGFR and HER3 in breast cancer is associated with worst outcome of the afflicted patients, which is attributed not only to the aggressiveness of such tumours but also to therapy resistance. Thus, in the present study we investigated the role of EGFR, HER2 and HER3 lateral signalling in cell migration by applying the MDA-MB-468-HER2 (MDA-HER2) breast cancer cell line, representing a valid model system. Knockdown of HER3 expression by siRNA resulted in decreased phosphorylated AKT (pAKT) levels, abrogated epidermal growth factor (EGF)-mediated PLC-?1 activation and a diminished EGF-induced migratory activity, depicting the interplay of EGF receptor (EGFR)/HER2/PLC-?1 and HER2/HER3/PI3K signalling in mediating the migration of EGFR/HER2/HER3-expressing breast cancer cells. Since therapy failure usually arises from metastatic cells, we further investigated whether HER3 signalling was active in established breast cancer disseminated tumour cell (DTC) lines as well as in primary DTCs derived from breast cancer patients. EGF treatment of DTC lines resulted solely in increased pAKT S473 levels, whereas in MDA-HER2 cells both pAKT S473 and pAKT T308 levels were increased upon EGF stimulation. Moreover, despite active HER3 molecules, as indicated by pTyr1222 staining, about 90% of analysed breast cancer patient DTCs exhibited very low or even no detectable pAKT S473 levels, suggesting that these cells might have fallen into dormancy. In summary, our data indicate the important role in EGFR, HER2 and HER3 lateral signalling in breast cancer cell migration. Moreover, our data further show that primary tumour cells and DTCs can vary in their HER activation status, which is important to know in the context of cancer therapy.
AB - HER2 signalling by heterodimerisation with EGFR and HER3 in breast cancer is associated with worst outcome of the afflicted patients, which is attributed not only to the aggressiveness of such tumours but also to therapy resistance. Thus, in the present study we investigated the role of EGFR, HER2 and HER3 lateral signalling in cell migration by applying the MDA-MB-468-HER2 (MDA-HER2) breast cancer cell line, representing a valid model system. Knockdown of HER3 expression by siRNA resulted in decreased phosphorylated AKT (pAKT) levels, abrogated epidermal growth factor (EGF)-mediated PLC-?1 activation and a diminished EGF-induced migratory activity, depicting the interplay of EGF receptor (EGFR)/HER2/PLC-?1 and HER2/HER3/PI3K signalling in mediating the migration of EGFR/HER2/HER3-expressing breast cancer cells. Since therapy failure usually arises from metastatic cells, we further investigated whether HER3 signalling was active in established breast cancer disseminated tumour cell (DTC) lines as well as in primary DTCs derived from breast cancer patients. EGF treatment of DTC lines resulted solely in increased pAKT S473 levels, whereas in MDA-HER2 cells both pAKT S473 and pAKT T308 levels were increased upon EGF stimulation. Moreover, despite active HER3 molecules, as indicated by pTyr1222 staining, about 90% of analysed breast cancer patient DTCs exhibited very low or even no detectable pAKT S473 levels, suggesting that these cells might have fallen into dormancy. In summary, our data indicate the important role in EGFR, HER2 and HER3 lateral signalling in breast cancer cell migration. Moreover, our data further show that primary tumour cells and DTCs can vary in their HER activation status, which is important to know in the context of cancer therapy.
KW - Animals
KW - Humans
KW - Female
KW - Mice
KW - Mice, Inbred BALB C
KW - Cell Line, Tumor
KW - Phosphorylation
KW - Transfection
KW - Neoplasm Invasiveness
KW - Signal Transduction
KW - Cell Movement
KW - RNA Interference
KW - Receptor, Epidermal Growth Factor/metabolism
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Receptor, erbB-2/metabolism
KW - Epidermal Growth Factor/metabolism
KW - Bone Neoplasms/enzymology/genetics/secondary
KW - Breast Neoplasms/enzymology/genetics/pathology
KW - Phosphatidylinositol 3-Kinase/metabolism
KW - Phospholipase C gamma/metabolism
KW - Receptor, erbB-3/genetics/metabolism
KW - Animals
KW - Humans
KW - Female
KW - Mice
KW - Mice, Inbred BALB C
KW - Cell Line, Tumor
KW - Phosphorylation
KW - Transfection
KW - Neoplasm Invasiveness
KW - Signal Transduction
KW - Cell Movement
KW - RNA Interference
KW - Receptor, Epidermal Growth Factor/metabolism
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Receptor, erbB-2/metabolism
KW - Epidermal Growth Factor/metabolism
KW - Bone Neoplasms/enzymology/genetics/secondary
KW - Breast Neoplasms/enzymology/genetics/pathology
KW - Phosphatidylinositol 3-Kinase/metabolism
KW - Phospholipase C gamma/metabolism
KW - Receptor, erbB-3/genetics/metabolism
U2 - 10.1002/path.3991
DO - 10.1002/path.3991
M3 - SCORING: Journal article
C2 - 22262199
VL - 227
SP - 234
EP - 244
JO - J PATHOL
JF - J PATHOL
SN - 0022-3417
IS - 2
M1 - 2
ER -
