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Targeted Therapies for Breast Cancer Tutorial

Inhibition of Estrogen Signaling

In This Section:

Estrogen Signaling in Normal Cells

Some of the earliest targeted therapies were aimed at disrupting the activity of the hormone estrogen in breast cancer cells.

In premenopausal women, estrogen is made primarily in the ovaries. However, estrogen is also made in smaller amounts by other tissues, including adipose (fat) tissue and the breast. Estrogen travels through the circulatory system to reach its target organs, which include the breast.

This is an image of a female body. Circulating estrogen is represented by small pink dots throughout the body. The ovaries are highlighted in pink to indicate that they are the primary source of estrogen in the female body.

During normal human development, the menstrual cycle, and pregnancy and lactation, estrogen and other hormones stimulate the growth and development of epithelial cells in the breast.

This is a side-view of a breast. The ductal system of the breast is shown extending from the nipple.

Estrogen is a steroid hormone that can easily cross the plasma membrane of the cell and then enter the cell's nucleus. Once inside the nucleus, estrogen binds to estrogen receptor proteins. The estrogen-receptor complex then binds to specific sequences of DNA and regulates the expression of numerous genes involved in cell growth.

A cross-section of a cell is shown. In the nucleus of the cell, estrogen, represented by pink spheres, is bound to estrogen receptor, represented by gray structures.

Estrogen Signaling in Cancer Cells

Many years ago, it was discovered that removal of the ovaries led to the regression of some breast tumors. It is now known that this occurred because the tumors were dependent on estrogen for growth.

A silhouette of a woman's body is shown in the background. A call-out bubble in the foreground shows a close-up view of breast tissue with a green mass in the middle representing a breast tumor.

Approximately 75% of breast tumors rely on estrogen. These tumors are referred to as "estrogen dependent." Tumors that do not rely on estrogen for growth are called "estrogen independent."

Estrogen dependence can usually be predicted by the presence of estrogen receptors in tumor cells. The estrogen receptor protein can be detected in breast tumor biopsy specimens using a technique known as immunohistochemical staining. Tumor cells that express estrogen receptors--called ER positive--are usually estrogen dependent. Tumors that lack estrogen receptors--called ER negative--are usually estrogen independent.

This is a split-screen image. The left panel is labeled, 'ER Positive: Estrogen Dependent.' There is a silhouette of a woman's body in the background covered with a picture of breast tissue stained for estrogen receptor. Cells with estrogen receptor are colored brown. The right panel is labeled, 'ER Negative: Estrogen Independent.' There is a silhouette of a woman's body in the background covered with a picture of breast tissue. There is a lack of brown staining, indicates  estrogen receptor is not present

Inhibiting Estrogen Signaling

Two different types of antihormone therapies are used to treat women with ER-positive breast tumors: selective estrogen receptor modulators and aromatase inhibitors.

Selective estrogen receptor modulators, or SERMs, which include drugs such as tamoxifen, compete with estrogen for binding to the estrogen receptor. When tamoxifen is bound to the estrogen receptor, estrogen is unable to bind, and estrogen signaling is disrupted.

This image shows a close-up view of the nucleus of a green cancer cell. Estrogen receptor, represented by a gray structure, is bound to a purple sphere representing tamoxifen. Estrogen, represented by a pink sphere, is unable to bind to estrogen receptor because of the presence of tamoxifen.

Aromatase inhibitors, which include drugs such as anastrozole, interfere with the body's ability to make estrogen. They do so by blocking the activity of aromatase, an enzyme needed for the final steps of estrogen production. Aromatase inhibitors do not work very efficiently in premenopausal women because the ovaries make too much aromatase. Therefore, they are used mainly in postmenopausal women.

Anti-hormone therapies such as tamoxifen and anastrozole can be used to treat most stages of breast cancer. Women with early-stage breast cancer are usually treated with surgery followed by antihormone therapy and radiation therapy, and sometimes chemotherapy.

A silhouette of a woman is shown on the left. A green mass in her right breast represents a breast tumor. On the right, a heading reads, 'Early-Stage Breast Cancer.' Bullets below the heading include surgery, anti-hormone therapy, radiation therapy, and chemotherapy.

Women with inoperable, metastatic breast cancer are often given antihormone therapy, with or without chemotherapy.

A silhouette of a woman is shown on the left. Her lymph nodes are highlighted. A green mass in her right breast represents a breast tumor. Additional green masses in other locations represent metastatic breast cancer cells in the lymph nodes, lung, and brain.

Antihormone therapies can also be used to reduce the risk of developing breast cancer. Tamoxifen and another selective estrogen receptor modulator, raloxifene, and several aromatase inhibitors have been found to reduce the risk of breast cancer among women at high risk for the disease.

More Information

Estrogen Activity

The following table lists several drugs that target estrogen activity and have been approved by the FDA for treatment of breast cancer and/or reduction of risk of breast cancer.

 Generic NameTrade Name(s)Type of Targeted Therapy
Selective estrogen receptor modulatorsTamoxifenNolvadex® Soltamox®Small molecule
 RaloxifeneEvista®Small molecule
 ToremifeneFareston®Small molecule
 FulvestrantFaslodex®Small molecule
Aromatase inhibitorsAnastrozoleArimidex®Small molecule
 ExemestaneAromasin®Small molecule
 LetrozoleFemara®Small molecule

Many drugs, including tamoxifen, that inhibit estrogen receptors in the breast can actually activate estrogen receptors in other tissues. For example, tamoxifen can activate estrogen receptors in the bone and endometrium. This is why these agents are called "selective estrogen receptor modulators," or SERMs, rather than estrogen receptor inhibitors. For more information on estrogen receptors and SERMs, visit NCI's Understanding Cancer Series: Estrogen Receptors/SERMs at http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors.

For more information on types of targeted therapies, see Understanding Targeted Therapies: An Overview at http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies.

Self Test

Questions

  1. Aromatase inhibitors act directly on the estrogen receptor.
    1. True
    2. False

Answers

  1. Correct Answer: b
    1. True - Incorrect.
      Aromatase inhibitors interfere with the activity of aromatase, the enzyme responsible for the final steps of estrogen production. They do not interact directly with the estrogen receptor.
    2. False - Correct.
      Aromatase inhibitors interfere with the activity of aromatase, the enzyme responsible for the final steps of estrogen production. They do not interact directly with the estrogen receptor.