Estrogen Receptors, Tamoxifen and Its Roles History And Future.
By Jose A. Garcia
News Articles
Breast Cancer Gene: Can the Breast Be Saved? In women with the breast cancer gene BRCA, breast-conserving therapy may be a "reasonable option," researchers say (msn news).
New Breast Cancer Drugs May Beat Tamoxifen (Monday, November 15, 2004) New Approach Used for Edwards' Breast Cancer (Wednesday, November 10, 2004) More Articles
Original literature of Tamoxifen 1, 2, 3.
History
Tamoxifen was first developed in 1962 as a morning-after birth control pill that was successful in experiments with laboratory rats.
Tamoxifen (brand name Nolvadex) is the best-known hormonal treatment and the most prescribed anti-cancer drug in the world.
Used for over 20 years to treat women with advanced breast cancer, tamoxifen also is commonly prescribed to prevent recurrences among women with early breast cancer.
Is a SERMs.
What Are Estrogens?
"Estrogens" are a family of related molecules that stimulate the development and maintenance of female characteristics and sexual reproduction.
The most prevalent forms of human estrogen are estradiol and estrone. Both are produced and secreted by the ovaries, although estrone is also made in the adrenal glands and other organs.
Estrogen Target Tissues
The breast and the uterus, which play central roles in sexual reproduction, are two of the main targets of estrogen.
Estrogen Receptors
An estrogen receptor is a protein molecule found inside those cells that are targets for estrogen action.
Therefore, when estrogen molecules circulate in the bloodstream and move throughout the body, they exert effects only on cells that contain estrogen receptors.
Estrogen Receptors Trigger Gene Activation
Estrogen receptors normally reside in the cell's nucleus, along with DNA molecules.
1. Estrogen molecule enters a cell and passes into the nucleus.
2. Bind to receptor3. Estrogen-receptor complex then
binds to specific DNA sites. 4. Attached to estrogen response
elements in DNA.5. Co activator proteins and more
nearby genes become active.6. MRNA produce( guide synthesis
of new proteins).7. Influence cell behavior in different
ways.
http://press2.nci.nih.gov
Estrogen-Induced Changes in Cell Behavior
In liver cells estrogen alters the production of proteins that influence cholesterol levels in the blood.
Cholesterol does not readily dissolve in blood, it bind to carrier proteins (Lipoproteins)
(LDL) bad cholesterol: release cholesterol directly onto the inner wall of arteries, creating the [plaque]
(HDL) inhibit formation of plaque and direct it to the liver.
Estrogen-Induced Stimulation of Cell Proliferation
Antiestrogen[Tamoxifen]
Anti-estrogens work by binding to estrogen receptors, blocking estrogen from binding to these receptors, stopping cell proliferation.
National Cancer Institute
SERMs
Selective estrogen receptor modulators, or SERMs.
They selectively stimulate or inhibit the estrogen receptors of different target tissues.
A SERM of this type would inhibit cell proliferation in breast cells, but stimulate the proliferation of uterine endometrial cells.
Tamoxifen Blocking Estrogen Receptors
Cell with estrogen receptors blocked by tamoxifen and helper proteins.
A estrogen receptor B tamoxifen C estrogen helper proteins D tamoxifen helper proteins E cell nucleus F DNA (genetic material) inside
cell nucleus
www.breastcancer.org/ tamoxifen_receptor.html
Estrogen Receptor
Breast cancers that DO have estrogen receptors are said to be "estrogen receptor-positive,“ (women who are past menopause)
Breast cancers that DO NOT possess estrogen receptors are "estrogen receptor-negative.“ (not governed by estrogen, or treated with tamoxifen. (premenopausal women)
In women with estrogen receptor-positive cancers, cancer cell growth is under the control of estrogen.
Therefore, such cancers are often susceptible to treatment with tamoxifen.
Tamoxifen and Cancer
Tamoxifen blocks the action of estrogen in breast tissue.
Tamoxifen bind to the estrogen receptors of breast cells, thereby preventing estrogen molecules from binding to these receptors.
The normal situation, when estrogen binds to its receptor, the binding of tamoxifen to the receptor does not cause the receptor molecule to acquire the changed shape that allows it to bind to coactivators.
As a result, the genes that stimulate cell proliferation cannot be activated.
How Hormonal Therapy Works
Hormonal therapy targets cancers that are fed by your own hormones. Like chemotherapy, hormonal therapy is a systemic—system-wide—therapy, which means that it affects cells throughout the body and your hair don’t fall.
If tests show that your breast cancer is responsive to your natural hormones, it will be described as estrogen receptor-positive or progesterone receptor-positive. This means that any remaining cells may continue to grow when these hormones are present in your body. Hormonal therapy may therefore be used to block the body’s natural hormones from fueling any remaining cancer cells.
Breast Cancer Genes: BRCA1 and BRCA2
Cancers cause cells in the body to change, to divide out of control (forming masses of tissue called tumors) and to spread to other parts of the body. They are named for the part of the body where they begin.
Breast cancer, the second major cause of death by cancer in American women, is often detected when there are visible changes in the breast, such as a lump, thickening, swelling, skin irritation or nipple discharge. The risk of breast cancer increases with age.
Genetics
Only 5 - 10 percent of all breast cancer cases are believed to have a genetic link. Of these, an estimated two-thirds are caused by mutations in either BRCA1 or BRCA2, genes thought to play a role in fixing damaged DNA. About 50 - 60 percent of individuals with certain mutations in either of these two genes will develop breast cancer by age 70.
Breast Cancer Treatment
The first step is to surgically remove the cancer from the breast.
It is difficult to be certain that every cancer cell has been removed at the time of surgery because some breast cancer cells could have spread to surrounding tissues or other organs prior to the operation.
Therefore, women often receive some type of treatment after surgery (adjuvant therapy) to prevent the growth of any cancer cells that might remain in the body.
Studies show that when tamoxifen is used for this purpose, the risk of cancer recurrence is reduced.
Tamoxifen and the Prevention of Breast Cancer
Breast-cancer prevention occurred in 1998 when the National Cancer Institute (NCI) announced results of a six-year study showing that tamoxifen reduced the incidence of breast cancer by 45 percent among healthy but high-risk women.
13,388 healthy women considered at high risk for breast cancer were recruited 85 developed breast cancer compared to 154 of those on the placebo or
dummy pill. potentially life-threatening side effects. There were 33 cases of endometrial
cancer in the tamoxifen group There were 30 cases of blood clots in major veins (deep-vein thrombosis) Because these problems developed exclusively among postmenopausal
women– 60-year-old, an age at which 17 out of every 1,000 women can be expected to
develop breast cancer within five years– ages of 35 and 59 were eligible to participate if their risks matched or exceeded those
of a 60-year-old
Side Effects
The National Cancer Institute estimates that the disease will develop among only 1/10th of 1 percent of women taking tamoxifen for five years. •Lower blood
cholesterol and therefore may lowerthe risk of heart disease.
Tamoxifen as a Cause of Uterine Cancer
Although tamoxifen has been useful both in treating breast cancer patients and in decreasing the risk of getting breast cancer.
Side effects arise from the fact that while tamoxifen acts as an antiestrogen that blocks the effects of estrogen on breast cells, it mimics the actions of estrogen in other tissues such as the uterus. Its estrogen-like effects on the uterus stimulate proliferation of the uterine endometrium and increase the risk of uterine cancer.
SOURCES
Journal of the National Cancer Institute, April 2, 2003
National Cancer Institute (http://www.nci.nih.gov)Proceedings for the 2003 Annual Meeting of the American Association for Cancer Research, April 8, 2003, Toronto, Canada
Abstracts from the 36th Annual Meeting of the American Society of Clinical Oncology, May 25, 2000, New Orleans, LA
Abstracts from the 17th Annual Miami Breast Cancer Conference, March 3, 2000, Miami, FL
American Cancer Society (http://www.cancer.org) http://www.intelihealth.com/IH/ihtIH/WSIHW000/8293/8354.html http://www.thebreastcaresite.com
