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Old 05-22-2014, 10:42 AM   #1
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Post Tamoxifen Mechanism

Tamoxifen Mechanism

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Tamoxifen competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues. Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal.
Tamoxifen itself is a prodrug, having relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen (endoxifen) which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself. These active metabolites compete with estrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor antagonist so that transcription of estrogen-responsive genes is inhibited.
Tamoxifen binds to estrogen receptor (ER) which in turn interacts with DNA. The ER/tamoxifen complex recruits other proteins known as co-repressors to stop genes being switched on by estrogen. Some of these proteins include NCoR and SMRT. Tamoxifen function can be regulated by a number of different variables including growth factors. Tamoxifen needs to block growth factor proteins such as ErbB2/HER2 because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers. Tamoxifen seems to require a protein PAX2 for its full anticancer effect. In the presence of high PAX2 expression, the tamoxifen/estrogen receptor complex is able to suppress the expression of the pro-proliferative ERBB2 protein. In contrast, when AIB-1 expression is higher than PAX2, tamoxifen/estrogen receptor complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.
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Old 05-22-2014, 10:44 AM   #2
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Re: Tamoxifen Mechanism

What is Tamoxifen?

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Tamoxifen is an antagonist of the estrogen receptor in breast tissue. It has been the standard endocrine (anti-estrogen) therapy for hormone-positive early breast cancer, although aromatase inhibitors have been proposed for postmenopausal women.
Some breast cancer cells require estrogen to grow. Estrogen binds to and activates the estrogen receptor in these cells. Tamoxifen is metabolized into compounds that also bind to the estrogen receptor but do not activate it. Furthermore tamoxifen prevents estrogen from binding to its receptor. Hence breast cancer cell growth is blocked.
Tamoxifen was discovered by ICI Pharmaceuticals (now AstraZeneca) and is sold under the trade names Nolvadex, Istubal, and Valodex. However, the drug, even before its patent expiration, was and still is widely referred to by its generic name "tamoxifen."
Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-menopausal women. Additionally, it is the most common hormone treatment for male breast cancer. It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease. It has been further approved for the reduction of contralateral (in the opposite breast) cancer.
Global sales of tamoxifen in 2001 were $1,024 million.
Since the expiration of the patent in 2002, it is now widely available as a generic drug around the world. Barr Labs Inc had challenged the patent (which in 1992 was ruled unenforcable) but later came to an agreement with Zeneca to licence the patent and sell tamoxifen at close to Zeneca's price.
As of 2004, tamoxifen was the world's largest selling hormonal drug for the treatment of breast cancer.
In the US, 20 mg tamoxifen tablets cost under $20 per month in quantity. In the UK, the NHS pays 1.90 a month (patients receive them either free or for the standard prescription charge of 7.10 in England, 4 in Scotland, 3 in Northern Ireland and free in Wales). Other countries report similar prices.
Comparative studies

In 2006, the large STAR clinical study concluded that raloxifene is equally effective in reducing the incidence of breast cancer, but after an average 4-year follow-up there were 36% fewer uterine cancers and 29% fewer blood clots in women taking raloxifene than in women taking tamoxifen, although the difference is not statistically significant.
In 2005, the ATAC trial showed that after average 68 months following a 5 year adjuvant treatment, the group that received anastrozole (Arimidex) had significantly better results than the tamoxifen group in measures like disease free survival, but no overall mortality benefit. Data from the trial suggest that anastrozole should be the preferred medication for postmenopausal women with localized breast cancer that is estrogen receptor (ER) positive. Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to anastrozole.
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Old 05-23-2014, 11:38 AM   #3
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Re: Tamoxifen Mechanism

and to repeat a former post from Rich66:

Re: PAX2 & AIB-1 in Taxmoxifen Resistance

Haven't heard much about this. Seems like clinically available testing is pretty limited to what's done in research. If I understand the below, simultaneously inhibiting aromatase may reduce TAM resistance. I know I just posted a bit on this in the endocrine+endocrine link which used TAM+Exemestane+Herceptin. I think green tea as well as chromium picolonate may inhibit aromatase. Here's a portal to endocrine issues.

Nature. 2008 Dec 4;456(7222):663-6. Epub 2008 Nov 12.
Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen.

Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS.
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Erratum in:
  • Nature. 2009 Feb 26;457(7233):1168.
Crosstalk between the oestrogen receptor (ER) and ERBB2/HER-2 pathways has long been implicated in breast cancer aetiology and drug response, yet no direct connection at a transcriptional level has been shown. Here we show that oestrogen-ER and tamoxifen-ER complexes directly repress ERBB2 transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. We implicate the paired box 2 gene product (PAX2), in a previously unrecognized role, as a crucial mediator of ER repression of ERBB2 by the anti-cancer drug tamoxifen. We show that PAX2 and the ER co-activator AIB-1/SRC-3 compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ER-PAX2 links these two breast cancer subtypes and suggests that aggressive ERBB2-positive tumours can originate from ER-positive luminal tumours by circumventing this repressive mechanism. These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer.

PMID: 19005469 [PubMed - indexed for MEDLINE]

Last edited by 'lizbeth; 05-23-2014 at 11:39 AM.. Reason: omission
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Old 05-23-2014, 11:41 AM   #4
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Re: Tamoxifen Mechanism

What is the official name of the PAX2 gene?

The official name of this gene is “paired box 2.”
PAX2 is the gene's official symbol. The PAX2 gene is also known by other names, listed below.
Read more about gene names and symbols on the About page.

What is the normal function of the PAX2 gene?

The PAX2 gene belongs to a family of genes that plays a critical role in the formation of tissues and organs during embryonic development. The members of the PAX gene family are also important for maintaining the normal function of certain cells after birth. To carry out these roles, the PAX genes provide instructions for making proteins that attach to specific areas of DNA and help control the activity (expression) of particular genes. On the basis of this action, PAX proteins are called transcription factors.
During embryonic development, the PAX2 gene provides instructions for producing a protein that is involved in the formation of the eye, ear, brain and spinal cord (central nervous system), kidney, and genital tract. After birth, the PAX2 protein is thought to protect against cell death during periods of cellular stress.

Does the PAX2 gene share characteristics with other genes?

The PAX2 gene belongs to a family of genes called homeobox (homeoboxes). It also belongs to a family of genes called PAX (paired box gene).
A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? in the Handbook.

How are changes in the PAX2 gene related to health conditions?

renal coloboma syndrome - caused by mutations in the PAX2 gene
More than 20 mutations in the PAX2 gene have been found to cause renal coloboma syndrome. Most mutations are specific to each affected family; however, one mutation has been found in multiple affected individuals. This mutation inserts one DNA building block (nucleotide) into the PAX2 gene (written as 619insG). Most mutations occur in the region of the protein that attaches to DNA, impairing its function as a transcription factor. A lack of functional PAX2 protein disrupts the formation of certain tissues (particularly the kidneys and eyes) during embryonic development, causing the signs and symptoms of renal coloboma syndrome.
cancers - associated with the PAX2 gene
Alterations in the expression of the PAX2 gene are associated with certain cancers. This altered expression is thought to enhance the gene's ability to protect cells from cell death, allowing for tumor growth (proliferation).
The PAX2 gene is abnormally active (overexpressed) in certain types of cancer of the kidney, prostate, breast, and ovary. Overexpression of the PAX2 gene is also seen in a rare form of kidney cancer called Wilms tumor and a soft tissue cancer called Kaposi sarcoma. Kaposi sarcoma causes cancerous lesions to develop under the skin and in mucous membranes (such as the moist lining of the mouth and digestive tract). Typically, high levels of PAX2 gene expression in cancer cells are associated with a more aggressive cancer.

Where is the PAX2 gene located?

Cytogenetic Location: 10q24
Molecular Location on chromosome 10: base pairs 100,745,710 to 100,829,940

The PAX2 gene is located on the long (q) arm of chromosome 10 at position 24.
More precisely, the PAX2 gene is located from base pair 100,745,710 to base pair 100,829,940 on chromosome 10.
See How do geneticists indicate the location of a gene? in the Handbook.

Where can I find additional information about PAX2?

You and your healthcare professional may find the following resources about PAX2 helpful.
You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the PAX2 gene or gene products?

  • paired box gene 2
  • paired box homeotic gene 2
  • paired box protein 2
See How are genetic conditions and genes named? in the Handbook.

Where can I find general information about genes?

The Handbook provides basic information about genetics in clear language.
These links provide additional genetics resources that may be useful.

What glossary definitions help with understanding PAX2?

cancer ; cell ; central nervous system ; digestive ; DNA ; embryonic ; gene ; gene expression ; kidney ; mucous ; mutation ; nervous system ; nucleotide ; ovary ; proliferation ; prostate ; protein ; renal ; sarcoma ; soft tissue ; stress ; syndrome ; tissue ; transcription ; transcription factor ; tumor ; Wilms tumor
You may find definitions for these and many other terms in the Genetics Home Reference Glossary.
See also Understanding Medical Terminology.

References (8 links)

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? in the Handbook.
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Old 05-23-2014, 11:48 AM   #5
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Re: Tamoxifen Mechanism

AIB1 expression predicted response to tamoxifen treatment in postmenopausal women

Weiner M. Ann Oncol. 2013;doi:10/1093/annonc/mdt159.

  • August 5, 2013
High levels of the estrogen receptor co-activator amplified in breast cancer 1 appeared to predict response to tamoxifen treatment among postmenopausal women with breast cancer.
See Also

Researchers also reported an association between amplified in breast cancer 1 (AIB1) expression and shortened RFS among women who did not undergo adjuvant treatment.
Prior studies have demonstrated between AIB1 and breast cancer survival, but the results have not been consistent.
In the current study, researchers randomly assigned 910 postmenopausal women to receive tamoxifen treatment or no adjuvant treatment.
The researchers used immunohistochemistry on tissue micro-arrays to analyze AIB1 protein expression.
Among patients with ER-positive breast cancer that expressed low tumor levels of AIB1, defined as less than 75%, researchers reported no significant difference in breast cancer-specific survival or RFS between those treated with tamoxifen and those who were assigned to the no-treatment arm.
Among patients with high AIB1 expression, defined as higher than 75%, researchers reported a significant decrease in breast cancer mortality (HR=0.38; 95% CI, 0.21-0.69) and recurrence (HR=0.40; 95% CI, 0.26-0.61) among those who underwent tamoxifen treatment. When adjusting for tumor size, progesterone receptor and HER-2 positivity, researchers found significant interaction between AIB1 and tamoxifen (P=.023).
Among untreated patients, high expression of AIB1 was significantly associated with shorter RFS (HR=1.74; 95% CI, 1.20-2.53), according to researchers.
“AIB1 has been shown to enhance the effects of estrogen, which may be in accordance with the view of AIB1 as a negative prognostic factor that at the same time predicts good benefit from tamoxifen,” the researchers wrote. “However, this study does not exclude that a minor subgroup of patients with ER-positive tumors simultaneously overexpressing AIB1 and HER-2 exhibit resistance to tamoxifen.”
Disclosure: The researchers report funding from the Swedish Cancer Society and the Swedish Research Council.
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Old 05-24-2014, 02:13 AM   #6
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Re: Tamoxifen Mechanism


Interesting. Don't forget Tamoxifen is not active but is a prodrug. The Enzyme CYP2D6 metabolizes Tamoxifen to the active drug, Nor Tamoxifen. CYP2D6 can be inhibited with drugs like Prozac, Paxil and Wellbutrin. (in generic terms-Fluoxetine, Paroxetine and Bupropion. These drugs can decrease the effect of Tamoxifen.

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