Thursday, January 10, 2013

TRIPLE NEGATIVE BREAST CANCER, A MELTING POT

The news that the Genome of triple negative breast cancer is similar to ovarian cancer has been good as a starting point. But that is as far as it goes!  Researcher are now scrambling trying to see how to best use this information and there is not one good direction.  In fact if anything, it may have complicated the landscape.
The controversy is compounded by the news that there is not simply a single type of Triple Negative Breast cancer.  This added to the fact that there is not just one type of Ovarian cancer.  So which one is the best approach?  And there are no known good suggestions, because of a lack of comprehensive database for cancer types.  Our cancer knowledge is disconnected.  Someone knows more about this. Someone else knows about that. There are Gaps in the knowledge which prevents us from moving forward.

Some of the facts and knowledge:

1. That the Genome is similar to Ovarian Cancer.
2. That Taxane-Cisplatin works in Ovarian Cancer
3. That PARP may have a role
4. That (low) MEKK1 expression is linked to tumor Response to Cisplatin.
5. That BRAC may impart a poor prognosis to the tumor
6. That Downregulation of STAT1 may play a role in the Oncogenesis of Triple Negative Breast cancer.
7. The almost total lack of Role of P53 alteration
8. Limited role of Kras Mutation
etc.

There are Major Questions of therapeutic importance:

1.Are these cancers MUCINOUS? Is there presence of MUC family members?
If these tumors are mucinous, this is another bad news.  Mucin presence shields against detection by the innate immune system and favors cancer dissemination to go undetected.  Mucin contains molecules that interfere with Glycocalyx, blunting their ability to expose cancer cells to the immune system, and also contain molecules full of Sulfhydryl expressing molecules which have profound interaction with electron based reactions at the membrane and Intracellularly.  These activities are generally protective for the cancer cell.

The Mucinous presence can also be supported by the presence of Galectin 4 (LGALS4)  19q13.3 (Heterozygosity site).   Positive TFF1 of the trefoil factor family which is an Estrogen regulated molecule that could potentially predict some response to hormone manipulation even in triple negative setting.

Amplification of CDX which modulate proliferation, cell adhesion and Apoptosis.  The fact is this CDX could be a driver phenomena as this cancer is known for its ability to have a steady progression.

OTHER Molecules of Importance CDH17, Tetraspanin, MSF1R, E-Cadherin and the Kruppel like factor.

2. These tumors seems to have a survival that is epic, raising the issue of expression of survival pathways MEK, MAP Kinases and C-jun
3. What differentiates Endometrioid Vs other ovarian cancers will play a role in this disease
4. What is the role of target therapy, important in Ovarian cancer, as it relates to Triple negative breast cancer?

We are only just scratching the surface of this problem,
Time to put the puzzle together!

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