HER2 Support Group Forums - View Single Post - important new article by Dr. Slamon et al

Lani · 01-15-2008, 10:08 AM

two sentences in that paragraph describe what Akt is--I won't even refer to the first word in each sentence as it seems the CENSORS are at work

You will just have to guess the two sentences!

expression is a word they use too describe the output of a protein which is a product of a gene (amplification is the word they use for too mamy copies of the gene, rather than the protein (its product), by the way)

Many proteins are enzymes which are like machines that make the body work by building things they make up, or breaking bigger things down (to the building blocks the cells need) or to stop something from working when there is already enough of it.

A common plan in the body is the use of adding or subtracting a phosphate group (phosphyrylation) to activate (turn on) or deactivate(turn off) function of a protein, especially an enzyme.

One of the deadliest pathways leading to cell proliferation (the source of uncontrolled growth of breast cancer) and there definitely can be more than one, and usually many..is the PI3K pathway which involves Akt. This pathway can be turned on by her2neu (but also by IGFR1) activation among others, but can also be turned on separately further down the pathway (sort of like a diagram by Rube Goldberg-- who showing how letting a marble go down a path could in turn make a lever launch a rubber ducky which ended up in a tub that overflowed which caused a spring to shoot an arrow in the air which ended up hitting a bulls eye) independently of her2neu, which would potentially be a reason for a patient doing poorly even if herceptin worked for them. So if Akt itself is overexpressed and activated whether by her2 neu having passed on the phosphorylation batton to it via the PI3K pathway like a relay rase, or having received the baton from elsewhere, the proliferation rate tends to become out of control . When her2 is negative and Akt is not activated or in low amounts, the proliferation rate is the least and these are least likely to metastasize and be aggressive. If her2+ER-
the difference in 5 yr survival (because of differences in proliferation rate and the propensity to metastasize, it is assumed) was found to be 20% if AKt was high vs 20% if it was low. In those her2+er+ prognosis was not good with or without high Akt, but was worse with high Akt at 10-15% 5 year survival.

Now these patients were from poor backgrounds, so it is unsure if they really took their tamoxifen, AIs (don't know if they were on medicaid, how hard it is to get prescriptions filled) and it doesn't say which got radiation therapy (although their metastatic rate far exceeded their rate of local recurrence, so that probably was not a major factor in their decreased 5 year survival). They did get their chemotherapy and surgery (and in the latter days of the study a few got herceptin, but perhaps late)

Again, I recommend the lecture of Dr. Osbourne whose link I posted in a thread around the holidays. It has great cartoons of the cascade from her2 on the cell surface through all the intermediate cascades to the nucleus and shows which ones have more to do with proliferation and which ones more to do with other functions of cancer cells (mobility, etc)

01-15-2008, 10:08 AM	#9
Lani Senior Member Join Date: Mar 2006 Posts: 4,780	two sentences in that paragraph describe what Akt is--I won't even refer to the first word in each sentence as it seems the CENSORS are at work You will just have to guess the two sentences! expression is a word they use too describe the output of a protein which is a product of a gene (amplification is the word they use for too mamy copies of the gene, rather than the protein (its product), by the way) Many proteins are enzymes which are like machines that make the body work by building things they make up, or breaking bigger things down (to the building blocks the cells need) or to stop something from working when there is already enough of it. A common plan in the body is the use of adding or subtracting a phosphate group (phosphyrylation) to activate (turn on) or deactivate(turn off) function of a protein, especially an enzyme. One of the deadliest pathways leading to cell proliferation (the source of uncontrolled growth of breast cancer) and there definitely can be more than one, and usually many..is the PI3K pathway which involves Akt. This pathway can be turned on by her2neu (but also by IGFR1) activation among others, but can also be turned on separately further down the pathway (sort of like a diagram by Rube Goldberg-- who showing how letting a marble go down a path could in turn make a lever launch a rubber ducky which ended up in a tub that overflowed which caused a spring to shoot an arrow in the air which ended up hitting a bulls eye) independently of her2neu, which would potentially be a reason for a patient doing poorly even if herceptin worked for them. So if Akt itself is overexpressed and activated whether by her2 neu having passed on the phosphorylation batton to it via the PI3K pathway like a relay rase, or having received the baton from elsewhere, the proliferation rate tends to become out of control . When her2 is negative and Akt is not activated or in low amounts, the proliferation rate is the least and these are least likely to metastasize and be aggressive. If her2+ER- the difference in 5 yr survival (because of differences in proliferation rate and the propensity to metastasize, it is assumed) was found to be 20% if AKt was high vs 20% if it was low. In those her2+er+ prognosis was not good with or without high Akt, but was worse with high Akt at 10-15% 5 year survival. Now these patients were from poor backgrounds, so it is unsure if they really took their tamoxifen, AIs (don't know if they were on medicaid, how hard it is to get prescriptions filled) and it doesn't say which got radiation therapy (although their metastatic rate far exceeded their rate of local recurrence, so that probably was not a major factor in their decreased 5 year survival). They did get their chemotherapy and surgery (and in the latter days of the study a few got herceptin, but perhaps late) Again, I recommend the lecture of Dr. Osbourne whose link I posted in a thread around the holidays. It has great cartoons of the cascade from her2 on the cell surface through all the intermediate cascades to the nucleus and shows which ones have more to do with proliferation and which ones more to do with other functions of cancer cells (mobility, etc)