IMPORTANT GENE INTERACTIONS II
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2.
*In order to control Triple Negative Breast cancer, you got to control the Wnt pathway!!!
Loss of PTEN desactivates BRAFeffect by abrogating BRAF induced oncogen driven Senescence
of cancer cells.
* ACTIVATION OF BRAF INDUCES BENIGN OR GOOD PROGNOSIS LESIONS, HOWEVER MELANOMA SUPPOSE ASSOCIATED ALTERATIONS IN THE PTEN AND THEREFORE THE PI3K SIGNALING PATHWAYS OPENING THE DOOR TO A ROLE FOR THE MTOR IN MELANOMA..

*NON INHIBITION OF THE MTOR LEAD TO SUPPRESSION OF THE p15INK 48 WHICH INCREASE TELOMERE STABILITY!

IF THIS IS TRUE, PROTECTION OR RESTORATION (activation) OF PTEN SHOULD PROTECT OR PREVENT MELANOMA!

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SUPPORTIVE EVIDENCES


2.1 

PTEN Loss Confers BRAF Inhibitor Resistance to Melanoma Cells through the Suppression of BIM Expression

Kim H.T. Paraiso1 et al.

"PI3K inhibitor enhanced BIM expression at both the mRNA and protein level and increased the level of apoptosis through a mechanism involving AKT3 and the activation of FOXO3a."

2.2  " Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma,"   Dankort et al.

3."β-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling. Highly metastatic tumors with β-catenin stabilization are very similar to a subset of human melanomas. Together these findings establish Wnt signaling as a metastasis regulator in melanoma"  Damsky et al.

• "β- catenin loss in Pten/Braf melanomas improves survival and inhibits metastasis
• β-catenin stabilization in Pten/Braf melanomas enhances metastasis
• Highly differentiated melanomas can be very metastatic in vivo
• β-catenin status in melanoma regulates PI3K/Akt and MAPK/Erk signaling"

2.4  " It has been reported that oncogenic activations of intracellular signaling pathways downstream of EGFR, including the RAS-RAF-MAPK and PI3K-PTEN-AKT signaling pathways, are important mechanisms for generating resistance to anti-EGFR MoAbs. In the RAS-RAF-MAPK pathway, active mutations of KRAS or BRAF are not uncommon"  Zhou et al
"The loss of PTEN expression, which was reported to occur in 19.0%–42.0% of Western and 30.0%–64.0% of Chinese CRC tumors, induces an increase in PIP-3 concentration and PIK3CA pathway activation"

2.5 "Beta-catenin Controls Metastasis in Braf-activated Pten-inactivated Melanomas" "beta-catenin levels control tumor differentiation and regulate both MAPK/Erk and PI3K/Akt signaling."

 

see the article.

2.6.

Abrogation of BRAF^V600E-induced senescence by PI3K pathway activation contributes to melanomagenesis PTEN depletion abrogates BRAF^V600E-induced senescence in human fibroblasts and melanocytes."

Liesbeth C.W. ET AL."

"  The PI3K pathway was often activated through either decreased PTEN or increased AKT3 expression in melanomas relative to their adjacent nevi. Pharmacologic PI3K inhibition in melanoma cells suppressed proliferation and induced the senescence-associated tumor suppressor p15^INK4B. This treatment also eliminated subpopulations resistant to targeted BRAF^V600E inhibition."

2.7

ICAM-1 Has a Critical Role in the Regulation of Metastatic Melanoma Tumor Susceptibility to CTL Lysis by Interfering with PI3K/AKT Pathway

1. Ahmed Hamaï1,
2. Franck Meslin1 ET AL.

  "More importantly, we found that the level of ICAM-1 expression by melanoma cells correlated with decreased PTEN activity. ICAM-1 knockdown in T1 cells resulted in increased phosphorylation of PTEN and the subsequent activation of AKT. We have additionally shown that inhibition of the phosphatidylinositol (3,4,5)-triphosphate kinase (PI3K)/AKT pathway by the specific inhibitor wortmannin induced a significant potentiation of susceptibility of G1 and ICAM-1 small interfering RNA–treated T1 cells to CTL-induced lysis. The present study shows that a shift in ICAM-1 expression, which was associated with an activation of the PI3K/AKT pathway, can be used by metastatic melanoma cells to escape CTL-mediated killing."

(PLEASE NOTE MART-1 AND ITS ROLE OR INTERACTION WITH PTEN!)