HER2 Phosphorylation Is Maintained by a PKB Negative Feedback

Loop in Response to Anti-HER2 Herceptin in Breast Cancer

Introduction:
The Scientist in this experiment are trying to determine why resistance occurs when
Herceptin is used in Monotherapy. This specifically is being used to treat the Tumors found in
Breast Cancer. They are proposing that the use of an inhibitor will resolve the problem of
resistance from Herceptin. The Inhibitors in question and under review are PanHER Inhibitor
and ADAM inhibitor. They believe using this inhibitor with Herceptin will allow Herceptin to
treat those with HER2 positive breast cancer effectively with no resistance.
ADAM17 was combined with Herceptin while phosphorylation was being inhibited they
believed they could retract the feedback loop and decrease HER2 phosphorylation. In this study
they found that Herceptin does not decrease HER2 phosphorylation1 They Built there study
around this result and sought to find the reason to why Herceptin is ineffective in decreasing
phosphorylation, and to find a treatment that would defeat Herceptin resistance.
Their study was ineffective in determining why Herceptin it being an antibody is unable to get
rid of HER2. It did however allow the protein ADAM17 to be created at an increasingly faster
rate by turning on a feedback loop. This was important and a giant leap for the study itself due to
the fact that ADAM17 Proteins release growth factors that activate the HER receptors and allow
maintenance and cell survival to take place.

1 HER2 Phosphorylation Is Maintained by a PKB Negative Feedback Loop in

Response to Anti-HER2 Herceptin in Breast Cancer. December 10,2010; Gijsen, King,
Perera, parker, harris, Larijani, Kong

Materials and Methods:

The Scientist tested on Cells that they got from a Cancer research Facility in the United
Kingdom. They placed the cells in different cultured solutions, and then took six-well plates and
brought the temperature of the cells down by placing them on Ice and rinsing them in Saline
Buffer. After washing the cells they then placed them in a lysis buffer for ten minutes.
Following the Lysis Buffer the cells were then dispersed into different temperatures. The
temperatures in which they used were first placed in 4 degrees Celsius and then boiled right after
at 95 degrees Celsius for 10 more minutes.
Once that process was complete the Cells were transferred to Gel and placed inside a
membrane. After this occurred they were washed multiple times in different percents of milk
solutions. As Cells grew and reached half their size they were monitored for protein growth
regularly. They did this in order to monitor the collaboration between HER and HER2.
Finally as cells reached full size they were treated with Herceptin for an hour. This
process continued many times at different temperatures and in different solutions.

Results:
The results were clear Herceptin is unable to eliminate HER2 phosphorylation in those
with HER2 positive breast Cancer Cells. These results were able to be determined after one hour
of Herceptin treatment.
However Herceptin treatments that are prolonged encourages phosphorylation of EGFR
and HER4 as well as the reactivating of HER32. The scientist studys also revealed that Ligand
2 HER2 Phosphorylation Is Maintained by a PKB Negative Feedback Loop in
Response to Anti-HER2 Herceptin in Breast Cancer. December 10,2010; Gijsen, King,

release helps to maintain HER2 by HER receptors. These HER Ligands are the key to giving
Cells their resistance to Herceptin. They were also able to determine that Herceptin helps
ADAM17 which withdraws the negative feedback loop from phosphorylation.

Discussion:
Herceptin was found to be ineffective in inhibiting HER2 and there was no evidence or proof
found that Herceptin decreases HER2. Herceptin was also unable to rid all stem cells, and the
ones that it did not rid maintained the HER2 phosphorylation. However long treatment did prove
in decreasing the ALDH positive stem cells.
It is unwise to consider HER receptors when seeking and Anti-HER treatment because of
their feedback network loops. This is because the feedback loop is activated when Herceptin is
present allowing Phosphorylation to be preserved.

Work Cited

Perera, parker, harris, Larijani, Kong, Pg. 2

1. HER2 Phosphorylation Is Maintained by a PKB Negative Feedback Loop in

Response to Anti-HER2 Herceptin in Breast Cancer. December 10,2010; Gijsen, King,
Perera, parker, harris, Larijani, Kong