Tuesday, September 30, 2008

Tamoxifen and Breast Cancer

 
When you get to my age, more and more of your female relatives, friends, and acquaintances will be diagnosed with breast cancer. They will be undergoing more or less radical surgery followed by chemotherapy and/or drug treatment. One of the most common drugs for the treatment of breast cancer is tamoxifen.

Tamoxifen is a chemical that binds to a protein called estrogen (or estradiol) receptor. The estrogen receptor is a protein that binds to DNA to increase (activate) or decrease (repress) gene expression. Its DNA binding properties are influenced by its interaction with the hormone estradiol (estrogen)—a discovery first reported by my friend Keith Yamamoto back in 1972 (Yamamoto and Alberts, 1972).

In normal cells, estrogen can stimulate the growth of tissues by turning on the genes that promote cell division. This is a good thing. However, it turns out that most of the breast cell cancers arise from cells that have estradiol receptors and in that case the presence of estrogen in your blood stream makes the cancer cells grow. These forms of cancer are called estrogen receptor positive (ER+) breast cancers.

That's the bad news. The good news is that such cancers respond well to tamoxifen. The effectiveness of tamoxifen is due to the fact that it binds to the estradiol receptor but doesn't convert it to the active regulator of gene expression.1 When you take tamoxifen there's so much more of it in your bloodstream that it out-competes all of the estrogen. As a result the cancer cells can't grow, (but neither can any of the other tissues that need estrogen).

Hormone therapy (tamoxifen) is often combined with radiation or chemotherapy to reduce the risk of recurring cancer for women who have undergone surgery to remove tumors. However, if the cancer has not spread to the lymph nodes then hormone therapy by itself is effective against ER+ breast cancer. This is especially true for pre-menopausal women 40 years of age or older where chemotherapy does not add significantly to the effectiveness of tamoxifen [see tamoxifen].


1. This isn't quite true. Tamoxifen itself doesn't bind to the estradiol receptor protein, instead it is converted inside your body to other chemicals that do bind.

Yamamoto KR, Alberts BM. 1972 In vitro conversion of estradiol-receptor protein to its nuclear form: dependence on hormone and DNA. Proc. Natl. Acad. Sci. USA. 69:2105-2109. [PubMed]

9 comments :

  1. The real controversy comes from taking tamoxifen (or raloxifene, which seems to be as or more effective, with fewer off-target effects) as prophylaxis for breast cancer is high-risk women. On the one hand, you're medicating otherwise healthy people. On the other hand, if you have four first-degree relatives with breast cancer, or are a confirmed BRCA1 or BRCA2 carrier, the chances of developing breast cancer is so high that it makes a lot of sense to protect yourself.

    Tamoxifen (and raloxifene), while not a perfect drug, has really revolutionized the treatment of ER+ breast cancer. Hopefully, as we begin to learn more and more about the molecular signatures of various cancers, similar targeted agents can be developed (e.g. Herceptin, Iressa, etc)

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  2. Tamoxifen itself doesn't bind to the estradiol receptor protein, instead it is converted inside your body to other chemicals that do bind.

    When you say "inside your body", do you mean inside or outside particular cells? Statements like that always seem really vague to me; is it known which cells, tissues, or organs carry out the conversion of tamoxifen and similar compounds?

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  3. Tamoxifen is converted into 4-hydroxytamoxifen by the CYP2D6 enzyme in the liver. 4-OH-Tam is the active metabolite. Most drugs work in this way; the drug you take is what is called a pro-drug, and is coverted into the bioactive compound by a set of liver enzymes known collectively as cytochrome P450 enzymes.

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  4. Also, don't forget to have you, your relatives, friends and acquaintances get your regularly scheduled colonoscopies. First one at age 50, then every 10 years thereafter (for those at average risk). Get the real colonoscopy, rather than the virtual one.

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  5. Most drugs work in this way; the drug you take is what is called a pro-drug, and is coverted into the bioactive compound by a set of liver enzymes known collectively as cytochrome P450 enzymes.

    Cool, thanks. I didn't realize that one family of enzymes is responsible for so much.

    Do these enzymes circulate in intercellular spaces in the liver, or do individual liver cells, er, ingest these pro-drugs and mix the enzyme with the pro-drug intracellularly?

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  6. Do these enzymes circulate in intercellular spaces in the liver, or do individual liver cells, er, ingest these pro-drugs and mix the enzyme with the pro-drug intracellularly?

    The latter. Most Cyt p450 enzymes are associated with the ER.

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  7. Get the real colonoscopy, rather than the virtual one.

    CT colonoscopy is a perfectly valid detection method, with a very high sensitivity (http://tinyurl.com/4ddbrl)

    Don't forget, colonoscopy is associated with fairly well-defined morbidities (colon perforation chief among them). Not saying virtual colonoscopy is a perfect replacement for colonoscopy, but it's getting there.

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  8. Not saying virtual colonoscopy is a perfect replacement for colonoscopy, but it's getting there.

    So get the real one today and by time you're ready for your next one in 10 years, maybe CT will have arrived.

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  9. Most Cyt p450 enzymes are associated with the ER.

    Thanks!

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