last up-date 2008-07-20 

        Already in the sixties the appearance of fetal proteins in cancer patients was discovered Abelev GI 1965, and described for cancer of the liver. Up to now for many cancers fetal or embryonic proteins are described, and for many of them it is known that they are made under the influence of progesterone, which is the typical steroid hormone of pregnancy. But this did not lead to a search for progesterone in patients with cancer most of whom are outside the age of pregnancy men or children. 

        A hint to the origin of the progesterone comes from the well known observation that many types of cancer, most prominent breast, prostate and colon cancer were extremely rare in peoples which did not use milk as food. That are the East Asians. Even Japanese who reach an age comparable or higher than those of Western industrialized countries did not get much of these diseases before picking up the use of milk-based food.

      But why? At the end of pregnancy progesterone production finishes and later milk production starts, one would assume as a dairy industry naive person.  

      That is very naive. It is possible to gain milk during pregnancy, too. And as it is possible, it is done. About 70% of the today produced milk comes from pregnant cows Rollinger M 2004 and this is the origin of  the ingested  progesterone Sato A 2006. Additionally to progesterone there are estrogenes in the same food  Courant F 2008 which often act synergistically in induction of tumor promoting markers. 

     After eating food like ice cream, cheese or butter a big increase in progesterone levels can become demonstrated a day later in the saliva Goodson WH 2007. In rats it was shown that the mRNA, a precursor of igf-1, a hormone linked to many kinds of tumors gets produced in the liver of rats feed with casein instead of plant protein Miura Y 1992. But not only rats, human breast cancer tissue to start to produce igf-1 under the influence of progesterone Milewicz T 2002.

      We take it up with milk products like milk, cheese, butter or cream in cakes, sweets, drinks and so on and so it comes that children, not pregnant women and man produce fetal proteins. Not only in cancer, but especially for cancer patients the progesterone is dangerous because progesterone is an immune modulation hormone which stops the immune reactions against the embryo. Natural killer cells have progesterone receptors and the contact between progesterone and this receptors leads to apoptosis, the organized death of the natural killer cells by a caspase mediated mechanism Arrovito L 2008.

     The same happens if cancer cells under the influence of progesterone start to produce embryonic proteins stopping the immune answer. 

Embryonic proteins often called tumor markers

CA15-3 

      The tumor marker CA15-3 mostly used to follow breast cancer  is an embryonic protein called MUC1. MUC1 is produced under the influence of progesterone McGuckin et al. 1998, Horne AW 2006 and and protects the embryo Braymann MJ 2007, by inhibiting cell lysis by natural killer cells Zhang K 1997. In cancer patients it stops the immune reaction against cancer cells and so the tumor is not disturbed to proliferate. CA15-3  is also up in other cancers but breast cancer for example prostate cancer where it is better known as MUC1 Li Y 2007. In Japan it is called Kl-6 and is used to monitor non small cell lung cancer Ishikawa N 2008 among others.

PIBF the proegesterone induced blocking factor 

      The more recently discovered progesterone induced blocking factor PIBF another tumor marker found not only in cancers but also in leukemia cells, too blocks the natural killer cells Check JH 2007. Here like with other tumor markers one finds a hint to their fetal or embryonic origin writing or reading the full name. For example CEA the often used tumor marker in colon cancer patients is the Carcino-Embryonic Antigen. 

       PIBF under physiologic condition plays its role in pregnancy, changing the regulation of the immune response, what is necessary to allow successful pregnancy Canellada A 2008. 

c-myc

     Another protein conventionally not called tumor marker but oncogene is c-myc. It too is more abundant in squamous cell cervical cancer patients with high progesterone Lindstrom AK 2007. 

VEGF

    Other fetal proteins like the vascular endothelial growth factor VEGF which is produced progesterone dependent too Mirkin S 2005 ,Hyder SM 2006 help the tumor to acquire blood vessels. Today we fight that in many diseases like colon cancer with antibodies like bevacizumab. But as these antibodies work only against one of many progesterone dependent proteins, the success is limited. The same VEGF associated process occurs during late diabetes where patients suffer from aberrant vascularization of the retina resulting in blindness or aberrant vascularization of kidney tissue resulting in the dependency on dialysis. 

      Of cause this process is not limited to diabetes or cancer patients which often do not live long enough to experience it. We see the same process in the eye of otherwise healthy people. There it is called wet age-related macular degeneration or macular edema and treated with a lot of VEGF directed antibodies Tremolada G 2007.

     Others progesterone induced proteins might provoke the insulin resistance known as diabetes type 2 which we often see in breast cancer patients during disease progression. The today produced milk is so rich in progesterone that it induces insulin resistance, hyperglycemia and glucosuria  in calves Hostettler-Allen RL 1994, which today have to be fed by milk replacer, because the milk of their mothers causes this disease also called diabetes type2.  

     In the pregnant women this change in metabolism may be necessary to keep the glucose in the blood in favor of the fetus. But, may be, even for the pregnant women the additional progesterone from food is deleterious. Many women on Western diet develop gestational diabetes and keep it after pregnancy.

     To find the diseases which might be involved one should look for progesterone dependent proteins. One easily finds VEGF in the medulloblastoma of children, of cause in breast cancer, in colon cancer, where anti-VEGF antibodies are approved for treatment and there is a wide array of other diseases. For example in the skin of persons with atopic disease there it a 25 fold increase in VEGF Zhang Y 2006 

Osteopontin

     A further new discovered protein trying to make a career as a tumor marker for mesothelioma the osteopontin is progesterone inducible too Mo SX 2007, Qu X 2008. In lung cancer its expression is linked to disease progression Guy SY 2007, and in breast cancer to lack of homone receptors Wang X 2008. It seems to promote metastasis of mammary tumors  Chakraborty G 2008 and it is associated with metastasis in renal cell carcinoma Ramankulov A 2007. 

   Like VEGF osteopontin is not only elevated in cancer, but in diabetes type 2 Belovici M 2007 where it is linked to calcification of blood vessels. Prednisolone probably competing for progesterone binding sites provides a certain relieve to osteopontin linked conditions like Erdheim-Chester disease Taguchi T 2008.

uPA, MMP-2, MM-9

     Elevated expression of osteopontin in higher grades of breast carcinoma correlates with enhanced expressions of several oncogenic molecules like uPA, MMP-2 and -9 Chakraborty G 2008 which can be stimulated by progestins too Carnevale RP 2007. 

    In the moment it is tried to use uPA as marker for therapeutic decision making in breast cancer. Women bearing breast cancer with low uPA unlikely to develop metastasis are encouraged to skip adjuvant chemotherapy. More interesting might be to teach breast and other cancer patients to change their cancer phenotype to a favorable one by avoiding progesterone rich uPA inducing food.  

Alkaline phosphatase 

      Alkaline phosphatase is mainly used as a tumormarker for prostate cancer. It can be tested to measure the effect of progesterone on progesterone sensible cells Zava DT 1998. During pregnancy bone alkaline phosphatase of the mother goes up Hellmeyer L 2006. The same occurs in patients with rheumatic arthritis Oelzner P 2007 and in cancer patients with bone metastases Lein M 2007.

TPS - tissue polypeptide-specific antigen 

     TPS also called cytokeratin-18 is a protein used as tumor marker is a protein found in maternal serum during pregnancy Protonotaiou E 2006

HLA-G

      Similar to the trophoblast protecting the embryo tumor-cells in vivo produce the progesterone inducible leucocyte antigen HLA-G  Urosevic 2008. This HLA-G is a progesterone inducible protein Yie SM 2006, not unlikely for a protein important during pregnancy. In tumor-cell-lines growing in vitro HLA-G cannot be observed Polakova K 2000 as the culture medium will not contain progesterone. 

      The HLA-G gene has a unique progesterone responsive element PRE with homology to the RNA tumor virus PREs Yie SM 2006 some suspicious,  some proven to induce human and animal tumors.

P-glycoprotein and breast cancer resistance protein

     P-glcoprotein and breast cancer resistance protein protect cancer cells by making them resistant to exogenous poisons administered during chemotherapy for cancer treatment. During embryonic development they perform this task in the placenta Mathias AA2005 

Transforming growth factor-beta 1

     Transforming growth factor-beta 1 (TGF-beta-1) is released progesterone dependent Kim MR 2005. Its production by tumor cells kills dendritic cells in sentinel lymph nodes draining breast cancers rendering the lymph nodes tolerant to invading tumor cells Ito M 2006.Elevated plasma TGF-beta1 levels correlate with decreased survival of metastatic breast cancer patients Ivanovic V 2006.

     Proteins repressed by progesterone which often do not work in tumor cells 

p53 

      A very interesting protein in general not called tumor marker, as it is often absent or not working in tumor cells, is p53. It looks as if gets repressed in persons with high progesterone levels Lindstrom AK 2007.

Heat shock protein 70

       It is not the only protein negatively controlled during pregnancy. Heat shock protein 70 is diminished in pregnant women Molvarec A 2007  In breast cancer patients it was shown to be most diminished in those women who quickly succumb to their disease Torronteguy C 2006. 

     Consumption of milk proteins and Cancer

    In April 2008 the Epic study on milk protein consumption development of prostate cancer was published Allen NE 2008. It was done in many Europe countries. Data from 1142 520 men got analyzed. It could be shown that prostate Cancer development increases 32% for every 35g of milk protein consumed. 

      Of cause, the researchers do not think that the protein itself is responsible for the cancer development. In the discussion they speculate about which hormone of the milk might be to blame. But IGF-1 a suspicious candidate increasing in blood after milk consumption will probably be destroyed in the stomach as proteins are in general.  So the researchers cannot explain their results. Physicians and epidemiologists from profession they are not familiar with modern milk production occurring during progesterone rich pregnancy of cows. But progesterone does not get destroyed in the stomach. And it seems to induce igf-1 Queiroga FL 2008 being one more progesterone induced protein. 

     What to do? 

     First to avoid milk products and to many progesterone rich eggs in the food and then of cause the future milk should be produced outside of pregnancy of the animals. That should be possible quickly and will improve the situation of seriously ill and still healthy persons who later might suffer under milk-born progesterone contamination.

     Long studies are not necessary. A patient for example with breast cancer will see a rapid decline in tumor markers like CA 15-3, a progesterone dependent protein which during pregnancy protects the embryo from natural killer cells. If all milk products are kept away from food, this diet, also known as Jane A. Plant Diet works. Probably if there is no interference by cortisones which protect the tumor cells too Mattern J 2007. And it does not work for breast cancer patients only. More quickly declines CA-125, the marker for cancer of the ovary (own experience).

Discussion

J Tatarinov discoverd alpha  fetoprotein as an antigen of hepatomas and embryos described by  Abelev GI 1965 in english

1965 Phil  Gold and Samuel O. Freedman discover the Carcino Embryonic Antigen CEA and describe that it is a fetal protein expressed between the  second and sixth month of fetal life Gold P 1965

Progesterone and disease, old text