Understanding Estrogen Receptors, Tamoxifen, and Raloxifene

What Are Estrogens?

"Estrogens" are a family of molecules. They stimulate the development of female characteristics and sexual reproduction. They are also responsible for their maintenance.

The natural estrogens produced by women are steroid molecules. That means they are derived from a particular type of molecular skeleton. It has four rings of carbon atoms. That gives them the shape shown here.

The most prevalent forms of human estrogen are estradiol and estrone. Both are produced and secreted by the ovaries. Estrone, though, is also made in the adrenal glands and other organs.

Estrogen Target Tissues

Estrogens are hormones. That means they function as signaling molecules. That kind of molecule travels through the bloodstream and interacts with certain cells. Those cells are in a variety of target tissues.

The breast and the uterus play central roles in sexual reproduction. They are two of the main targets of estrogen. Estrogen molecules also act on the brain, bone, liver, and heart.

Estrogen Receptors

Estrogens act by binding to parts of cells. Those parts are called estrogen receptors. These are protein molecules that are found inside cells that are targets for estrogen action. They contain a specific site where only estrogens (or closely related molecules) can bind.

All target tissues of estrogen molecules contain estrogen receptors. Other organs and tissues in the body do not. Estrogen molecules can only affect cells that contain estrogen receptors.

Estrogen Receptors Trigger Gene Activation

Estrogen receptors are normally in the cell's nucleus. That’s where DNA molecules are as well. DNA contains the cell’s genes.

When there are no estrogen molecules, estrogen receptors are inactive. They have no influence on DNA. When an estrogen molecule enters a cell and passes into the nucleus, it binds to its receptor. That causes the shape of the receptor to change. The estrogen-receptor complex binds to coactivator proteins. This causes nearby genes become active. The active genes make molecules of messenger RNA. These guide the synthesis of specific proteins. The proteins can then influence cell behavior in different ways. How depends on the type of cell involved.

Estrogen-Induced Changes in Cell Behavior

In liver cells, estrogen alters the making of proteins that influence cholesterol levels in the blood.

Cholesterol does not readily dissolve in blood. Before it can be transported through the body, it becomes bound to special cholesterol-carrying proteins. These are called lipoproteins. The liver produces two different types. One is called low-density lipoprotein (LDL). The other is high-density lipoprotein (HDL). LDL-cholesterol is said to be the "bad" form of cholesterol. It tends to release cholesterol directly onto the inner wall of arteries. That creates the "plaque" that can lead to heart disease. HDL is said to be the "good" form of cholesterol. It restricts the formation of plaque. It also carries cholesterol away from the arteries and back to the liver.

Estrogen's effect on liver cells increases the amount of HDL cholesterol. It also decreases the amount of LDL cholesterol. By doing those two things, it helps to lower the risk of heart disease.

Estrogen-Induced Stimulation of Cell Proliferation

In some target tissues, the main effect of estrogen is to cause cells to grow and divide. This is a process called cell proliferation.

In breast tissue estrogen triggers the growth of cells that line the milk glands. This prepares the breast to produce milk if the woman becomes pregnant.

Estrogen also promotes proliferation of the cells that form the inner lining of the uterus. This inner lining is called the endometrium. The growth of these cells prepares the uterus for an embryo to be implanted. If a woman does not become pregnant, estrogen levels fall dramatically at the end of the menstrual cycle. The endometrium disintegrates. As it does, it is shed from the uterus and vagina in a bleeding process called menstruation.

Estrogen and Cancer

Estrogen can provide both benefit and harm.

The main benefits include its roles in:

  • programming the breast and uterus for sexual reproduction
  • safeguarding the heart by controlling cholesterol production in ways that limit the buildup of plaque in the arteries
  • preserving bone strength by helping to maintain the proper balance between bone buildup and breakdown

But estrogen can also cause harm. The most serious problem comes from the ability of estrogen to promote cell proliferation in the breast and uterus. Doing this is one of estrogen's normal roles. But it can also increase a woman's chance of getting breast or uterine cancer.

Estrogen and Breast Cancer

During each cycle, estrogen triggers the making of cells that line the inside of milk glands in the breast.

At the end of each monthly cycle, estrogen levels drop if a woman does not become pregnant. Without high estrogen levels, the milk gland cells deteriorate and die. Another cycle of cell proliferation and cell death occurs the next month. The period from puberty to menopause lasts about 40 years. This means the average woman has hundreds of cycles of breast cell division and cell death.

But how do these cycles increase the risk of having cancer?

Cancer Arises from DNA Mutations in Cells

Cancer is caused by DNA mutations. It comes from damage in genes that regulate cell growth and division.

Some mutations are inherited. Others are caused by exposure to radiation. Or they may be caused by exposure to mutation-inducing chemicals. For instance, the chemicals in cigarette smoke can do this. Mutations also can occur spontaneously. That happens when mistakes are made when a cell duplicates its DNA molecules.

Specific genes, such as proto-oncogenes or tumor suppressor genes, control proliferation. When mutations of these cells occur, the changes are copied with each new generation of cells. More mutations in these altered cells can lead to uncontrolled proliferation. That causes the onset of cancer.

Estrogen-Induced Proliferation of Existing Mutant Cells

Estrogen does not appear to cause the DNA mutations that trigger the development of human cancer. But estrogen does stimulate cell proliferation.

One or more breast cells may already have a DNA mutation that increases the risk of developing cancer. Then estrogen will cause these cells to proliferate along with normal breast cells. The result will be an increase in the total number of mutant cells. Any of these cells might later acquire the additional mutations that lead to the onset of cancer.

In other words, estrogen-induced cell production leads to an increase in the total number of mutant cells that exist. These cells are at increased risk of becoming cancerous. So the chances that cancer may actually develop are increased.

Estrogen-Induced Proliferation and Spontaneous New Mutations

A woman might not have any mutant breast cells. Estrogen-induced proliferation of normal cells could still increase the risk of cancer.

The reason involves DNA. A cell must duplicate its DNA prior to each cell division. That ensures the two new cells that result will receive one complete set of DNA molecules. But from time to time there are mistakes in the process of DNA duplication. So the resulting DNA copies may contain a small number of errors. If one of these spontaneous mutations occurs in a gene that controls cell growth and division, it could lead to cancer.

Proliferation of normal cells from exposure to estrogen creates a vulnerability to spontaneous mutations. Some of these might represent a first step on the pathway to cancer.

Estrogen and Uterine Cancer

Estrogen triggers the production of cells that line the uterus. This happens during each menstrual cycle. It’s followed by the death of these cells during menstruation. Over 40 years, hundreds of cycles occur.

These repeated cycles increase the risk of cancer in the same ways they do in the breast:

  • Estrogen can stimulate the division of uterine cells that already have DNA mutations.
  • It also increases the chances of developing new, spontaneous mutations.

It doesn’t matter whether the mutations are inherited or spontaneous. Cell production will increase the number of these altered cells. That can lead to uterine cancer.

Antiestrogens

Estrogen can promote the development of cancer in the breast and uterus. So it seems logical that substances that block the action of estrogen might help in prevent these two types of cancer. It would also seem they might be useful in treating them. So scientists have worked to develop "antiestrogen" drugs. These are drugs that can block the action of estrogens. By doing so, they interfere with, or even prevent, the proliferation of cancer cells.

Antiestrogens work by binding to estrogen receptors. This blocks estrogen from binding to them. This also blocks estrogen from activating genes for specific growth-promoting proteins.

SERMs

While working to develop antiestrogens, scientists made a surprising discovery. Some drugs that block the action of estrogen can actually mimic it in other tissues.

That’s because estrogen receptors of different target tissues vary in chemical structure. So estrogen-like drugs can interact in different ways with receptors in different tissues. These drugs are called selective estrogen receptor modulators. They’re also called SERMs. They selectively stimulate or restrict the different estrogen receptors. For instance, a SERM might restrict the estrogen receptor in breast cells. But it might also activate the receptor in cells lining the uterus. That means it would restrict cell production in breast cells. But it would also stimulate production in the uterus.

Tamoxifen and Cancer

The first SERM to be studied for its anticancer properties is a drug called tamoxifen.

Tamoxifen blocks the action of estrogen in breast tissue. It exerts this antiestrogenic effect by binding to the estrogen receptors of breast cells. When it does, it prevents estrogen from binding to these receptors. But when tamoxifen binds to the receptor, it does not cause the receptor to acquire the changed shape estrogen would. So it can’t bind to coactivators. As a result, the genes that stimulate cell production won’t be activated.

Tamoxifen and Breast Cancer Treatment

In breast cancer, proliferation of the breast cancer cells is often driven by estrogen.

Tamoxifen can block the effects of estrogen on breast cells. So scientists predicted that breast cancer could be treated by using tamoxifen. Tamoxifen was first approved for such use in breast cancer treatment in the 1970s.

The first step in treating breast cancer is to surgically remove the cancer from the breast. It is difficult, though, to be certain that every cancer cell has been removed. Some breast cancer cells could have spread to surrounding tissues. Or they could have spread to other organs prior to the operation. That’s why women often receive some type of treatment after surgery. This is known as adjuvant therapy. The goals is to prevent the growth of any cancer cells that might still be in the body. Studies show that when tamoxifen is used the risk of cancer recurrence is reduced.

Research is still being done to improve the effectiveness of using tamoxifen for treatment.

Estrogen Receptor-Negative Breast Cancer

Cancer cells in the breast do not always have receptors for estrogen.

Breast cancers that do are said to be "estrogen receptor-positive." Those that do not are "estrogen receptor-negative." With estrogen receptor-positive cancers, cell growth is controlled by estrogen. So these cancers can often be treated with tamoxifen.

With estrogen receptor-negative cancer, cell growth is not governed by estrogen. So it is not treated with tamoxifen.

Tamoxifen and Breast Cancer Prevention

Tamoxifen can reduce the risk of cancer coming back after breast cancer surgery. That raises the question of whether it might also help prevent breast cancer. Using tamoxifen to block the action of estrogen in the breast in healthy women might decrease a woman's risk of cancer in the future.

The NCI did a study involving more than 13 thousand healthy women. They were all at high risk for breast cancer. That risk was based on their family or medical history. Half the women were given tamoxifen. The other half were given a placebo. After 5 years, the group receiving tamoxifen had a lower rate of breast cancer.

Tamoxifen as a Cause of Uterine Cancer

Tamoxifen has been useful in treating breast cancer patients. It has also been useful in decreasing the risk in women with high risk. But it also has some serious side effects.

In some tissue, like the breast, tamoxifen blocks the effects of estrogen on breast cells. In other tissue, like the lining of the uterus, it mimics the actions of estrogen. Its effects on the uterus stimulate cell production of the lining. That increases the risk of uterine cancer.

The Need for Better SERMs

Tamoxifen functions as a SERM. It selectively blocks or stimulates the estrogen receptors of different target tissues. It acts like estrogen in the uterus. It also can lower LDL cholesterol levels. It also can preserve or increase bone density in women who have gone through menopause. Thus, aside from its tendency to increase the risk of uterine cancer, it has a number of potential benefits.

Scientists are actively working on the development of other SERMs. The goal is to keep the same benefits without the harmful effects.

Hormone Replacement During Menopause

SERMs may be important for women who have passed through menopause. That’s because they now produce little estrogen.

The lack of estrogen is linked to several health problems. For instance, estrogen has positive effects on blood vessels. It also has positive effects on bones. When estrogen levels decrease, women are at increased risk for heart disease. They also have increased risk for osteoporosis. Osteoporosis is a weakening of the bones. It causes them to become more vulnerable to fractures.

Many women take hormone pills after menopause. These pills contain estrogen. They take the pills to strengthen bones and help control other symptoms. But they may also subject themselves to the harmful effects of estrogen. For instance, they increase their risk for breast and uterine cancer. Adding progesterone to the pill can eliminate the increased uterine cancer risk. But there is evidence that progesterone may increase breast cancer risk.

Search for the Perfect SERM

Scientists are looking for SERMs that can mimic the benefits of estrogen without its harm.

The ideal drug would have a positive effect on bones, heart, and blood vessels. But it wouldn’t harm the breast and uterus.

Faslodex is the first of a new class of agents. They’re called estrogen receptor down regulators. It causes the estrogen receptor to be infolded into the cell nucleus. That way it can no longer be stimulated. The drug has been effective in post-menopausal women who have tamoxifen resistance. It lacks any estrogen-like activity, though.

Raloxifene and the Prevention of Osteoporosis

One SERM that may exhibit some of these properties is raloxifene. This drug is approved by the FDA for preventing osteoporosis.

It seems to function like estrogen in bone. It acts to maintain bone strength and increase bone density. Plus, it resembles estrogen in being able to lower LDL cholesterol levels. That lowers the risk of heart disease.

Information on the drug’s long-term risks and benefits is limited. But preliminary evidence suggests it may work without increasing a woman's risk of cancer.

Raloxifene and the Prevention of Cancer

In animal studies, raloxifene has already been shown to reduce both breast and uterine cancer. And in early human trials, it has reduced the risk of breast cancer without the unwanted effects in the uterus that tamoxifen has. The STAR trial found that it was as effective as tamoxifen in reducing the risk of invasive breast cancer. But it also had a non significant higher risk of noninvasive breast cancer. The risk of other cancers was similar for both drugs.