p38MAPK-activated AKT in HER-2 overexpressing human breast cancer cells acts as an EGF-independent survival signal.

BACKGROUND

HER-2 is an epidermal growth factor receptor (EGFR) family receptor tyrosine kinase that is overexpressed in about 30% of human breast cancers correlating with a poor prognosis. Previous work in our laboratory has found that HER-2 overexpression plays a role in growth factor independence, anchorage independence, motility, and invasion of naturally occurring basement membranes. We also found that AKT was activated by p38MAPK in these cells, but this activation did not play a role in invasion. Since AKT has been shown in other systems to be a survival factor, we hypothesized that HER-2 mediated activation of AKT is necessary for growth factor independence.

METHODS

Human mammary epithelial cells transduced to overexpress HER-2, HER-2, PTEN, and Myr-AKT and the primary breast cancer cell lines SUM-149 and SUM-225 were used to dissect the signaling pathways leading to growth factor independence and anchorage-independent growth in HER-2 overexpressing cells.

RESULTS

We found that, in the absence of EGF, p38MAPK-activated AKT is necessary for HER-2 overexpressing cells to survive and to form colonies in soft agar. We show that EGF works as a survival signal in the absence of p38MAPK-mediated activation of AKT. We also show that human mammary epithelial cells expressing a constitutively active AKT do not require EGF for growth or colony formation in soft agar.

CONCLUSIONS

The data presented here indicate that AKT activation can compensate for EGF-mediated cell survival signals leading to growth factor independence and anchorage-independent growth.