Yet Another Point of Confusion

[Tom]

Here's a link to another article that left me scratching my head. This cell signalling stuff just gets weirder and weirder.


http://www.oncolink.com/resources/article.cfm?c=3&s=8&ss=23&Year=2005&Month=12&id=12592

[AlaskaAngel]

Interesting, if deadly. Well, perhaps it acts one way with one type of bc and the opposite way with another type of bc? Which might mean it still could be used as a treatment agent if inhibition was applied to the right set of patients and promotion applied to others?

[RhondaH]

and I TOO was blown away by it. Not sure how it affects Her2? Anyone else make heads or tails of it?

Rhonda Hoffman

[al from Canada]

I think a lot of the cell motility has to do with cellular surface adhesion qualities, ie the higher the adhesion factor, the less motility. If down regulating AKT causes down regulation of the adhesion factor, you have a problem but until you are sure of why the problem exists the problem, you are no closer to a solution.

Al

[Unregistered]

My very limited experience is the more you read and delve the more your realise how complex it all is, how many mechanisms are involved, the multi layered multipathway, multi mechanism nature of it all.

You also begin to realise how much the scientific community does not know.

It is truly wonderous what they have found but it looks like a very long way to go yet. As the article says;

"Dr. Toker said this research "once again reminds us of the immensely complex nature of molecular events which govern the behavior of cancer cells. Proteins such as Akt, which at first glance seemingly control only one aspect of a cancer cell's life, actually have multiple functions."

I looked up ACT and breast cancer on google. As usual fro any such subject a heap of links.

Here are a couple;

http://www.medscape.com/viewarticle/503916_9

ABSTRACT

"Mammalian Target of Rapamycin and the PI3K/Akt Pathway

The PI3K pathway is involved in regulating multiple cellular functions important for cell survival and proliferation. Signaling through Akt regulates the serine-threonine kinase mammalian target of rapamycin (mTOR). mTOR is involved in transcriptional and translational regulation proteins important to regulation of the cell cycle. In breast cancer, the PI3K/Akt/mTOR pathway can be activated by the ER, the IGF-1 receptor, and the HER family, especially HER3. Oncogenic ras is another stimulator of this pathway.[46] Also, in a study of 70 primary breast cancer specimens, 40% had an activating mutation in the PI3KCA gene.[47"


AND if you really wan't to end up "scratching your head" how about this?

http://clincancerres.aacrjournals.org/cgi/content/abstract/9/8/2933

[al from Canada]

that said,

My personal (totally uneducated) opinion is that the P13K pathway is critical to HER2 mediation, FYI...curcumin is a P13k inhibitor
Al

[Unregistered]

Abstract re above link - Possibility of Tamoxifen enhancing growth (again) in particular circumstances.

I am none the clearer. I recognised other pathways I have read about in the google highlights relating to AKT. All I do know is that it is all very complex, which begs questions as to single target drugs, and what else they may do we do not know about yet good or bad. Caution is again the word I think.

It all seems to me to make a strong argument for making the best of what nature provides, and whose side effects we know something about as a base point.

Tom if you want to go hunting look up PPAR alpha and gamma, which has a lot to do with fat metabolism and digestive pathways. Also endothelin which seems to have a role in pregnancy stem cells etc. It is fascinating. Both have roles in breast cancer and I have seen reports that expression levels are omega three six sensitive.

Welcome to a "mind boggoling" arena, the smallest part of which is proabably a lifetimes work.

ABSRACT



Experimental Therapeutics, Preclinical Pharmacology
Expression of Constitutively Active Akt-3 in MCF-7 Breast Cancer Cells Reverses the Estrogen and Tamoxifen Responsivity of these Cells in Vivo1
Jesika Faridi, Lihong Wang, Gerda Endemann and Richard A. Roth2

Department of Molecular Pharmacology, Stanford University, 269 West Campus Drive, Stanford, California 94305-5174

Purpose: Prior studies had suggested that Akt activity is elevated in a subset of breast cancers. In this study, to test the effect of active Akt-3 on estrogen receptor function, we have produced MCF-7 cells, which express active Akt-3 and examined the estrogen responsiveness of these cells in vivo and in vitro.

Experimental Design: MCF-7 cells expressing active Akt-3 were studied for estradiol (E2) responsiveness in vitro by both using an estrogen receptor element reporter construct as well as looking at induction of endogenous genes. These cells were also studied in vivo after injection into nude, ovariectomized mice by following tumor growth rates in the presence or absence of E2, tamoxifen, or the pure antiestrogen, ICI 182,780 (fulvestrant).



Results: Akt-3-expressing cells were found to produce tumors in mice in the absence of E2 that were approximately equivalent in size to control cells in mice given E2. Moreover, the formation of tumors by the Akt-3 cells was greatly suppressed by E2, stimulated by tamoxifen, and unaffected by ICI 182,780. In the in vitro assays for gene induction by E2, the Akt-3-expressing cells exhibited similar E2 and tamoxifen responsiveness as the control cells.

Conclusions: These results indicate that expression of active Akt-3 in MCF-7 cells results in E2-independent tumor growth. Moreover, the growth of these tumors is inhibited by E2 and enhanced by tamoxifen. Finally, these tumors are resistant to ICI 182,780. These findings suggest that the amount of active Akt present in breast cancers may be important in the relative efficacy of different treatments."