Role of the aging vasculature and Erb B-2 signaling in epidermal growth factor-dependent intravasion of breast carcinoma cells.
BACKGROUND
The risks for developing breast carcinoma and dying from the disease increase with age. Mortality from breast carcinoma usually is due to metastatic disease. Metastatic cells are able to invade into the vascular tissue in a growth factor-dependent manner. Because breast carcinoma mortality increases with age, examination of breast carcinoma interactions with young and aged endothelial cells is essential.


METHODS
We studied a series of breast epithelial cells (HMT-3522 cells) that exhibited either noninvasive characteristics (S-1 cells) or epidermal growth factor (EGF)-dependent invasive characteristics (T4-2 cells).


RESULTS
Increased invasion of HMT-3522 cells was observed across an aged rat brain microvascular endothelial cell (BMEC) monolayer that was isolated from aged rats (24 months) compared with young rats (age 1 month). This increased invasion was inhibited by the specific EGF receptor inhibitor, AG1478, and by the Erb B-2-specific inhibitor, AG825. To analyze further the contribution of Erb B-2 to the EGF-dependent invasion of HMT-3522 cells, T4-2 cells were treated with the Erb B-2-specific therapeutic antibody trastuzumab and with the specific inhibitor AG825 and were then assayed for invasion. Both inhibitors led to a significant decrease in EGF-dependent invasion. Erb B-2 expression was found to be elevated in T4-2 cells ( approximately 5-fold higher) compared with S-1 cells. However, treatment of T4-2 cells with the specific Erb B-2 inhibitor, AG825, failed to inhibit EGF-mediated signaling to phosphatidylinositol 3-kinase or extracellular-regulated kinases 1 and 2.


CONCLUSIONS
The current study findings indicate that aging of endothelium may contribute to the invasive phenotype of breast carcinoma cells and that "cross-talk" between Erb B-2 and EGF receptor is required for the intravasion of these cells into the surrounding vasculature.
Price
Daniel J
DJ
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA.
Avraham
Shalom
S
Jiang
Shuxian
S
Fu
Yigong
Y
Avraham
Hava Karsenty
HK
D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology*; D011233:Precipitin Tests; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D018719:Erb-b2 Receptor Tyrosine Kinases