Modern science has extensive insights into biochemical processes in the human body.
But in my opinion, the findings are often not sufficiently and quickly enough recognized. Doctors only receive treatment guidelines after many years, if not even decades later. Teaching content at the universities usually lag behind many years of current research.
The fact that a certain receptor is more frequently found in more than 50% of breast cancer patients is long known. It is the so-called macrophage-stimulating 1 receptor (MST1R) [1]. It is also called Ron receptor tyrosine kinase. This Ron receptor is more detectable in breast cancer cells. Patients possessing this receptor more frequently (overexpression) tend to have a higher level of metastases and a lower survival chance. [2]
The MST1R or Ron receptor must be activated by a substance that is docked to this receptor. Such a substance is called a ligand. The only known ligand for the Ron receptor is the hepatocyte growth factor-like protein (HGFL). Pro-HGFL is converted by the enzyme matripase to the active ligand HGFL. If both substances (HGFL and matripase) are multiplied (overexpression), then the prognosis of the breast cancer patients is significantly worsened. This is understandable due to the fact that HGFL activates the Ron receptor [3].
Activation of the Ron receptor promotes uncontrolled cell growth (cell proliferation), spread of the tumor cells in the body (cell migration), and invasion of the tumor cells into various organs and tissues (invasion). [4]
Indications point to the fact that the negative effects of the Ron receptor on tumorigenesis require the molecule β-catenin [5]. Β-catenin is not to be confused with β-carotene or catechol.
This β-catenin signal axis is more active in many human breast cancers than in patients who do not have breast cancer. The prognosis is even worse the more active this signal axis is. β-catenin can be activated through different pathways. RON induces, for example, the phosphorylation of certain substances which promote β-catenin. [6]
A test tube experiment with tumor cells showed that RON-mediated tumor growth and metastasis could be prevented by the withdrawal of β-catenin. This indicates that a lesser quantity of β-catenin does not have a negative effect mediated through the Ron receptor. [6]
The comprehension of this RON-β-catenin signal axis can be an important step in the understanding of aggressive breast tumors. It can lead to new therapeutic approaches.
The Vitamin D Receptor (VDR) and Breast Tumor
The VDR is a receptor for the hormone 1.25 vitamin D3. 1.25 vitamin D3 is made from vitamin D3. Vitamin D3 is produced in the skin by UV irradiation or by consuming food supplements. The opinion still exists that vitamin D3 must first be activated in the kidney and the liver. Actually, apparently every body cell is able to activate vitamin D3. This activation and the docking onto the VDR is essential for the human body and its integrity. The sun basically gives each cell the signal “hello, outside the sun is shining, and you (the cells) are a part of this whole process, so submit yourself”.
For what other reason should the body have developed this system? After all, one could activate the VDR directly.
If the VDR is activated by 1.25 D3, it protects against breast cancer formation, as well as of the deterioration of an already existing tumor. The VDR also protects against metastization and controls cell growth. Controlled cell death of a mutant tumor cell is initiated (apoptosis), differentiation of the cell is regulated and the vascular supply (vascularisation) which is important for tumor growth is inhibited. [7]
The activated VDR inhibits the described β-catenin by increased formation of E-cadherin (upregulation of transcrition) [8]. Activation of β-catenin can be inhibited by DKK-1 (Dickkopf related-protein 1). DKK-1 is increased by the VDR. [9]
Thus, VDR inhibits tumorigenesis and tumor growth by lowering β-catenin levels and by reducing the β-catenin target genes.
The VDR (vitamin D3 receptor) activated by 1.25 vitamin D3 could thus reduce the aggressiveness of breast cancer mediated by RON.
Correspondingly, vitamin D3 substitution leads to reduced breast cell growth, decreased metastatic spread and infiltration into organs and tissues in breast tumor cells which show an increased RON receptor. Thus, an artificially generated activation of β-catenin could reverse the positive effect of 1.25 vitamin D3.
Unfortunately, the incredible properties of the VDR (vitamin D receptor) are too little known (not much known) largely unknown. It is also important to know that the VDR can not be activated by vitamin D3 alone. Substances such as resveratrol and curcumin also have an important influence on the VDR. Firstly by a direct activation, but also on the expression of the VDR (this leads to the increase of the VDR density). Consequently, substances such as vitamin D can have a better effect.
Resveratrol and curcumin have a wide range of effects. Natural substances often have manifold effects. In contrast, drugs often have a single effect but a number of side effects.
[1] Maggiora P, Marchio S, Stella MC, Giai M, Belfiore A, De Bortoli M, Di Renzo MF, Costantino A, Sismondi P, Comoglio PM. Overexpression of the RON gene in human breast carcinoma. Oncogene. 1998;16:2927–2933.
[2] Lee WY, Chen HH, Chow NH, Su WC, Lin PW, Guo HR. Prognostic significance of co-expression of RON and MET receptors in node-negative breast cancer patients. Clin Cancer Res. 2005;11:2222–2228.
[3] Welm AL, Sneddon JB, Taylor C, Nuyten DS, van de Vijver MJ, Hasegawa BH, Bishop JM. The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:7570–7575.
[4] Gaudino G, Follenzi A, Naldini L, Collesi C, Santoro M, Gallo KA, Godowski PJ, Comoglio PM. RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. The EMBO journal. 1994;13:3524–3532.
[5] Danilkovitch-Miagkova A, Miagkov A, Skeel A, Nakaigawa N, Zbar B, Leonard EJ. Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta-catenin pathway. Molecular and cellular biology. 2001;21:5857–5868
[6] Wagh PK, Gray JK, Zinser GM, Vasiliauskas J, James L, Monga SP, Waltz SE. beta-Catenin is required for Ron receptor-induced mammary tumorigenesis. Oncogene. 2011;30:3694–3704.
[7] Lopes N, Paredes J, Costa JL, Ylstra B, Schmitt F. Vitamin D and the mammary gland: a review on its role in normal development and breast cancer. Breast Cancer Res. 2012;14:211
[8] Orsulic S, Huber O, Aberle H, Arnold S, Kemler R. E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation. Journal of cell science. 1999;112:1237–1245
[9] Aguilera O, Pena C, Garcia JM, Larriba MJ, Ordonez-Moran P, Navarro D, Barbachano A, Lopez de Silanes I, Ballestar E, Fraga MF, Esteller M, Gamallo C, Bonilla F, Gonzalez-Sancho JM, Munoz A. The Wnt antagonist DICKKOPF-1 gene is induced by 1alpha,25-dihydroxyvitamin D3 associated to the differentiation of human colon cancer cells. Carcinogenesis. 2007;28:1877–1884.