my eyes glazed over reading this. is there a summary available? :)

[log in to unmask] wrote:  From the most recent Paleo Diet Newsletter

"I recently spoke at a conference at Harvard organized by Walter Willet, focused on dairy. As the science unfolds, we continue to uncover more information that the National Dairy Council is not going to like. It turns out that there may be much greater concerns than its high insulinemic response, recombinant bovine growth hormone, casein protein, or lactose intolerance. In this issue, I update you on my latest findings regarding how dairy can adversely affect your health.

ANOTHER REASON NOT TO DRINK YOUR MILK: BETACELLULIN 

Although dairy foods comprise nearly 11% of the energy in the typical U.S. diet (1), these foods were never consumed by every human on the planet as recently as 500 human generations (10,000 years) ago. Increasingly, data from tissue, human, animal and epidemiological studies demonstrate that this staple food has the potential to adversely influence health as would be predicted by the evolutionary template.

The Epidermal Growth Factor Receptor

Only 12 short years have elapsed since the discovery that humans bear a hormonal receptor in their gastrointestinal tract called the epidermal growth factor receptor. This trans-membrane, hormonal receptor is very unusual in that it is expressed luminally – meaning that it faces the gut contents rather than the bloodstream (2, 3). The location of the EGF receptor puzzled scientists for years – why was it expressed luminally and what was its function (4)? Since, hormones always arrive at tissues from the circulation, why should the EGF receptor face the gut contents, which in effect are outside the body?

Function of the Gut Epidermal Growth Factor Receptor

It turns out that the primary function of the luminally facing EGF receptor is to stimulate healing and maintain the integrity of the cells lining the gastrointestinal tract (3, 4). In humans, the primary source of the hormone (EGF) which binds to the EGF receptor in the gut comes from saliva (5). So when you swallow your own saliva, it contains a hormone (EGF), which binds to the EGF receptor located in the gut to maintain the integrity and promote healing of the cells (epithelial cells) lining the gut (Figure 1).
After the salivary EGF binds the EGF receptor, both the receptor and EGF may cross into the interior of gut cells. The EGF receptor is then recycled back into the cell membrane (Figure 1). Most of the EGF is degraded by organelles within the cell called lysosomes. However, some EGF escapes destruction by the lysosomes and then enters circulation. We know that salivary EGF enters circulation, because when the salivary and submandibular glands of laboratory animals are destroyed, blood concentrations of EGF are greatly reduced (6). 


Figure 1. Synthesis of EGF from the salivary glands and absorption in the gut via the EGF receptor (EGF-R).



Besides being expressed luminally in the gut, the EGF receptor is expressed in the usual manner (facing the bloodstream) in all epithelial cells and organs undergoing branching morphogenesis during embryonic development. Consequently salivary EGF that enters the circulation can bind EGF receptors located in the skin, gastrointestinal tract, lung, kidney, mammary gland, pancreas, prostate gland, ovary and other tissues. At this point, it should be noted that there are actually four different forms of the EGF receptor (ErbB-1, ErbB-2, ErbB-3 and ErbB-4) found throughout the body. Each of these four receptors combine with one another to form pairs called homodimers or heterodimers that can bind EGF or EGF like hormones (Figure 2). Keep this information in mind when the discussion moves to cancer.

Figure 2. The four families of the epidermal growth factor receptor (ErbB1, ErbB2, ErbB3 and ErbB4). 
Each of the four receptors combines to form a pair with a different receptor (a heterodimer) or itself (a homodimer). The 10 hormones which can bind the various receptors are depicted in boxes above the receptors. Their binding specificities are indicated by the arrows. 



Healthy normal adults secrete on average 0.48 ml of saliva per minute (7) which translates to 28.8 ml per hour or 691 ml per 24 hours. The average concentration of EGF in whole saliva (not just the protein fraction) is 0.0512 nanograms per ml (8); so the total salivary EGF produced in a 24 hour period would equal on average 35.3 nanograms.

Betacellulin: A Hormone that Binds the Epidermal Growth Factor Receptor

The EGF receptor is a promiscuous receptor in that it doesn’t just bind a single hormone (EGF), but rather binds a large family of hormones including transforming growth factor alpha (TGF-á), heparin binding EGF(HB-EGF), epiregulin (EPR), amphiregulin (AR), neuregulins 1, 2, 3 and 4 (NRG1, NRG2, NRG3, NRG4) and betacellulin (BTC) (9). The key hormone to remember here is betacellulin because it is found in cow’s milk in high concentrations. Betacellulin is a very stable hormone in that it is not degraded by the heat of pasteurization and is even found in high concentrations in cheese (10).

When you drink cow’s milk or eat cheese, you are, in effect, dosing yourself with betacellulin. You might think that protein shearing enzymes in your gut would breakdown betacellulin and other hormones belonging to the EGF hormonal family before they can get to the gut EGF receptor. However, this is not the case, as cow’s milk contains peptidase inhibitors which allow EGF to remain intact even in human digestive juices of the stomach and small intestine (11). Remember that betacellulin can bind the luminally expressed EGF receptor in the gut, and can thereby enter circulation via the same mechanism that the salivary hormone, EGF, does. 

So what – what if a little betacellulin from cow’s milk gets into your bloodstream – does it matter? You bet it matters. A liter of whole milk (633 kcal) contains 1,930 nanograms of betacellulin (10) whereas the amount of EGF that your salivary glands secrete is only 35.3 ng per day. The binding affinity of betacellulin to the EGF receptor is greater than that for EGF; consequently betacellulin can displace EGF from the EGF receptor (9). The amount of betacellulin that you get from drinking even a single cup of milk (457 nanograms) has the capacity to stimulate the EGF receptor 10 times more than what normally would occur during a 24 hour period from EGF in saliva. 

The Epidermal Growth Factor Receptor and Cancer

So, what’s wrong with increased stimulation of the EGF receptor? First off, when a member of the EGF hormonal family binds the EGF receptor it sets off a chemical cascade that ultimately causes more EGF receptors to be synthesized. This process is known as up-regulation. Higher concentrations of EGF up-regulate the EGF-R (12, 13). So, by ingesting supplemental betacellulin from cow’s milk, the number of EGF receptors may increase in the gut and in peripheral tissues bearing the EGF receptor. A higher betacellulin concentration in the bloodstream along with increased numbers of EGF receptors causes an increase in signaling (flux) through the EGF receptor pathway.

Overexpression of the EGF receptor and hence increased flux through this pathway occurs in a wide variety of cancers including: breast, colon, prostate, ovarian, lung, pancreatic, bladder, stomach, and head and neck cancers (13, 14, 15). Higher concentrations of the EGF receptor increases cancer recurrence, reduces survival and increases tumor progression and development (13). Activation of the EGF receptor by the EGF family of hormones, including betacellulin, promotes cancer by 1) increasing cell proliferation, 2) decreasing programmed cell death (apoptosis), 3) increasing tumor formation and progression and, 4) increasing growth of blood vessels (angiogenesis) within tumors (14).

The U.S. Food and Drug administration has recently approved experimental trials of pharmaceuticals (gefitinib, erlotinib, cetuximab) which can halt or slow various cancers by blocking the EGF receptor signaling (14, 15). Perhaps a better strategy would be to stop drinking betacellulin containing cow’s milk which may over stimulate EGF receptor signaling in the first place. Although observational epidemiological studies cannot show cause and effect between diet and disease, they suggest that milk drinking and dairy consumption is linked to a variety of cancers including: ovarian (16-19), breast (20-26), colon (20, 27-29), lung (20, 30-32), stomach (20, 33), pancreatic (34-36), and prostate (37-40). Milk, indeed, may not be good for everybody, particularly cancer patients or those with a family history of cancer."


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