(estradiaol, estriol, estrone) are steroid hormones found in both men and women. In women, estrogens are produced mostly by the ovaries and are responsible for female secondary sex characteristics and menstruation. In men they are produced in the testes and regulate sperm growth and in a possible interplay with androgens may drive libido. In both sexes they also found to coordinate the regulation of fat levels, lung health, and fluid balance.
The Estrogens’ link to malicious cell growth is not new for they are long associated with breast, ovary, liver and pancreas cancers. A good example of how estrogen can cause things to go awry is with breast cancer: In healthy female breast tissue high estrogen levels during menstruation cause the propagation of cells that line the milk glands. When estrogen levels fall following the end of menstruation, the cells die and are absorbed by the body. The mechanism by which this happens is this: estrogen molecules in the blood enter a cell and bind to a protein called the Estrogen Receptor (ER)
(see, we scientist do sometimes give them obvious names!) and like a switch, ER turns on the genes in charge of cell growth of the milk gland lining.
Since cancer is a disease in which a mutation in cell growth genes causes uncontrolled growth, as shown in the figure above, it is easy to see how in the ~500 times a woman menstruates in her lifetime that one propagated mutation can eventually wreak havoc on those cells.
The gallbladder is a small pear shaped sack located under the liver. The liver creates a digestion aid called bile that is stored and concentrated in the gallbladder. When digesting food, the gallbladder contracts and releases the bile into the intestine to break down fats from your diet. Since fat (think of oil or butter) is not soluble in water, the bile contains special salts and cholesterol derived acids that surround the fat and increases its ability to be absorbed by your body.
GBC is uncommon and has been found to be difficult to diagnose early on due to its overlapping symptoms with other diseases. If GBC is discovered early, drug treatment is pretty much nonexistent and the usual remedy consists of surgery to remove the cancerous gallbladder. In the average 10-15 years it takes to become fully diseased and therefore discovered, the cancer has usually become aggressive and spread to other organs, leaving a rather grim prognosis.
Until now what may be causing GBC was the usual vague cancer causing suspects: could be genetic, could be environmental (pollutants, etc), could be the stars were aligned incorrectly, etc. A review of the literature shows several journal articles reporting a correlation with gallstones
in post-menopausal woman using hormone (i.e. estrogen) replacement therapy as well as women using birth control. It was Gustafsson and his group that finally connected the dots and noticed a critical common ingredient: GBC occurs more frequently in women and therefore estrogen may be playing an important role in the development of GBC.
What The UH Team Did
One of the main proteins responsible for the activation of bile creation is a not too distant relative of the ER called the Liver-X-Receptor
(LXR). There are two forms of LXR, named LXR alpha (LXRa) and LXR beta (LXRb). LXRa is found exclusively in the digestive organs (liver, spleen, kidneys, intestines), fat cells, and lungs. In the liver, LXRa is activated by metabolized cholesterol and turns on the genes needed to synthesize bile salts/acids. LXRb is found in all tissues and is involved in regulating fat, sugar and cholesterol levels. A possible association between ER’s
is that they both have roles in regulating cholesterol.
When the researchers tested male and female mice lacking LXRa, LXRb or both proteins, they found that the gallbladders of only the female mice missing the LXRb protein were infected, swollen, and pre-cancerous. With this clue Gustaffson’s team figured that since cancer is a metabolic disease where the cells grow uncontrollably, the next logical stones to look under should be the proteins involved with regulation of cell growth. Indeed upon checking, the team found that the pathway involved in cell growth and adhesion to be severely defective in the mice missing LXRb. Finally, they made the LXRb/estrogen/gallbladder cancer connection by testing female mice lacking LXRb and had their ovaries (the main production organ of estrogens in females) removed and sure enough found no evidence of gallbladder precancerous growth.
This is the first time a biochemical association between estrogens and GBC has ever been demonstrated. This is very promising news for those diagnosed with GBC because a new option is to now target LXRb for drug treatment. It will be exciting to see Gustafsson’s team as they determine how estrogens interplay with LXRb and the cell growth proteins.