The invasive and metastatic transformation of
cancers often results in death. However, the mechanisms that promote this transformation remain unclear. Two closely related receptors, the
epidermal growth factor receptor (EGFR) and ErbB2, are overexpressed in a significant percentage of breast and prostate
carcinomas, among others, with this up-regulated signaling correlating with
tumor progression. Previous studies in our laboratory have demonstrated that an EGFR-
phospholipase C (
PLC)gamma-mediated motility-associated signaling pathway is rate-limiting for
tumor cell invasion in vitro and in vivo in one model of prostate
carcinoma. Therefore, we investigated whether this PLCgamma signaling pathway also was rate-limiting for invasion in other tumor cell lines and types and whether this EGFR activity is subsumed by the closely related ErbB2. We determined the effects of PLCgamma signal abrogation by pharmacological (
U73122) and molecular (expression of the dominant-negative PLCz) means on the in vitro invasiveness of
tumor cells. Inhibition of PLCgamma signaling concomitantly decreased invasiveness of de novo-occurring transgenic
adenocarcinoma mouse prostate (TRAMP) lines and the human
breast cancer cell lines MDA-468 and MDA-231; these lines present up-regulated EGFR signaling. Because the prostate and
breast cancer lines usually present autocrine stimulatory loops involving EGFR, we also examined transgenic
adenocarcinoma mouse prostate C1 and MDA-468 treated with the EGFR-specific
kinase inhibitor
PD153035 to determine whether invasiveness is dependent on EGFR signaling.
PD153035 reduced invasiveness to levels similar to those seen with
U73122, suggesting that the autocrine EGFR stimulatory loop is functioning to promote invasiveness. To determine whether this signaling pathway also promotes invasiveness of ErbB2-overexpressing
tumors, we examined the human
breast carcinoma line MDA-361; again,
U73122 inhibition of PLCgamma decreased invasiveness. In all situations, the inhibition of PLCgamma signaling did not decrease mitogenic signaling. Thus, the motility-associated PLCgamma signaling pathway is a generalizable rate-limiting step for
tumor cell progression.