PART I (speculative thoughts)
1.It is increasingly recognized that the development of the triple negative breast cancer is linked to abnormalities of gene expression at the Wnt (& NOTCH) pathways, abnormal levels of Cytokines/growth factors and perturbances or predisposition to autoimmune diseases (AS SUGGESTED BY THE bASAL LIKE CELL MORPHOLOGY which comes from autoimmune component involvement)!
The various genetic pathways involved provide tremendous opportunities for target therapy interventions. Testing through clinical trials and laboratory studies appear to be the main ways to ascertain the effectiveness of proposed interventions.
Here we submit the Hypothesis that a known Anti-JAK-2 in combination with both an Anti-c-MET and an Anti-VEGF could slow down the metastatic progression of triple negative breast cancer and secondarily have a role in inflammatory breast cancers.
We are also going to identify through this study other opportunities of therapeutic interventions as we discuss the flow of causal events leading to the malignant transformation of Breast cells.
2.Potential Pathophysiology in these Breast Cancers.
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2.1 As women enter the reproductive age, with the advent of Menarche, starts a period of their lives with increased Estrogen production. It has been reported (K-S et al) that" Estrogens have been shown to markedly modulate the immune system...mostly by regulating " namely IL-2 and Interferon-gamma. The increase of these cytokines was driven through the modulation of their promoter activities.
It is worth mentioning here that IL-4 production was not increased by this Estrogen surge.
N. et al suggested that under Estrogen stimulation "the production of interferon-gamma was enhanced by E2 stimulation. And that E2 increases not only the number of cells expressing IFN-gamma but also the IFN-gamma levels in each cells". These authors did emphasize that the enhancement of interferon was through the Estrogen Receptor (ER) ie ER alpha, beta and mERs.
The positive regulatory feedback loop between Interferons and Estrogen Receptor-alpha was also the focus of work reported by R. et al. Indeed "patients with Systemic Lupus Erythematosis, an Autoimmune disease, AFFECTING WOMEN OF CHILD BEARING AGE, were found to have an even more of an increase in Interferon-gamma which increases levels of Receptors for Estrogen. This Estrogen Receptor response was driven through "activation of signal transducers and activation of Transcription 1 (STAT1) by Interferon".
(This provide the link to autoimmune diseases, It also means that all of the sudden you have a period of life with high Estrogen with too many receptors, you know they will be a "violent" desensitization of these receptors which in fact you will not find in Triple negative Breast Cancers which happen in women of "child bearing age").(And here comes the intervention of the STATS! with STAT5a the more specific one!)
2.2Overexpression of TNF is also induced by Estrogen
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Kod... et al:
"Certain autoimmune diseases are also associated with excess levels of Tumor Necrosis Factor-TNF alpha, and Anti-TNF drugs are known to be useful". The elevation of TNF alpha is known to activate the NF-kB pathways. (HERE COMES CYTOKINES' EXPANSION). And through the MAPK, the same activation will reach the JNK which leads to transcription of C-jun and ATF2, opening the door to cell proliferation.
Wikipedia suggests that TNF also can lead to"induction of death signaling and therefore could be pro-Apoptotic" but remember this is the thing taken care of by SMAD4-E3 which help escape proliferative control! The path to Neoplastic proliferation is set!
Through the Ubiquitins comes also the involvement of the NOTCH!
(see for yourself NOTCH-MAML1-EP300..........ubiquitins 8---E3 (RNF 41)
and with the NOTCH comes in the Wnt, loss of cellular boundaries and shape, and "consensus" to survive!
Continuing here!
Estrogen is known to "upregulate TNF production by increasing the number of TNF producing cells"
AND IN BREAST CANCER BIOLOGY, THE ELEVATION OF TNF SYNERGIZES THE ELEVATION OF INTERFERON gamma EFFECT ON CTGF/CCN2 (SCH...et al!)
this is the same CCN that drive by chemotaxis bone metastatic invasion 9 and metastasis is driven! wonder why the bone marrow is an early relatively "irrelevant" metastasis ! (keep you knives where they are, I see you ready to brandish them!). Science is talking for now!
TO BE CONTINUED ....BY
2.3. TNF, INTERFERON-gamma, JAK-2, AND CCN2.
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