Breast Cancer, drug resistance, and biopharmaceutical targets
Curator: Larry H Bernstein, MD
UPDATED 5/24/2026
Is a gene of tamoxifen metabolism a predictive biomarker for tamoxifen response?
Summary: CYP2D6 metabolized tamoxifen in the liver to enoxifen, which binds with more affinity to the estrogen receptor that tamoxifen. Genetic testing has not shown definitive results as CYP2D6 as a predictive biomarker of response however some studies show otherwise.
Source: https://www.cancertodaymag.org/cancer-talk/cyp2d6-gene-tamoxifen-effectiveness/
Can the CYP2D6 Gene Affect Tamoxifen’s Effectiveness?
A recent analysis examined whether CYP2D6 metabolism influences tamoxifen response. The answer isn’t entirely clear.
by Ashley P. Taylor
May 19, 2026
Can the CYP2D6 Gene Affect Tamoxifen’s Effectiveness?
Image by Martin Philip / iStock / Getty Images Plus
MANY PEOPLE with early-stage hormone receptor-positive breast cancer receive maintenance tamoxifen after surgery to reduce their risk of cancer coming back. This hormone therapy, which is usually taken for five to 10 years, works by blocking estrogen receptors on cells so that estrogen cannot bind to cancer cells and spur their growth.
But tamoxifen itself binds only weakly to estrogen receptors. The drug becomes active after the liver converts tamoxifen into another molecule called endoxifen, which binds estrogen receptors more tightly than tamoxifen. The protein that converts tamoxifen into endoxifen is called cytochrome P450 2D6, or CYP2D6 (pronounced “sip-two-dee-six”).
A meta-analysis published Feb. 6, 2025, in Cancer Epidemiology, Biomarkers & Prevention, shows that women with breast cancer who were treated with tamoxifen and had less metabolically active CYP2D6 protein had an increased risk of poorer treatment outcomes than those with normal CYP2D6 activity. In the study, which looked at 33 clinical trials and grouped patients according to their CYP2D6 status, poor CYP2D6 metabolism was associated with a 28% increased risk of recurrence or death compared with normal CYP2D6 metabolism.
Looking at the results of the study, “you can see that patients who have lower or less CYP2D6 activity do seem to have worse outcomes from tamoxifen treatment,” says Daniel Hertz, a clinical pharmacologist at the University of Michigan College of Pharmacy, who was not involved in the research. “This association has been long speculated and has been extremely challenging to validate in clinical studies,” he adds.
The Research on CYP2D6 and Endoxifen
There are more than 100 different variants of the CYP2D6 gene, which provides the genetic blueprint for the protein that metabolizes tamoxifen and many other drugs. The versions of the CYP2D6 gene that patients inherit—their CYP2D6 genotype—influence how actively the CYP2D6 protein metabolizes drugs. Pharmacogenomic testing, which analyzes a person’s genes to predict response to medications, can identify these genetic variants. Based on these tests, patients can be classified as poor, intermediate, normal or ultrarapid metabolizers.
Studies show that people taking tamoxifen who have lower CYP2D6 activity generally have lower levels of endoxifen in their bloodstream, but research findings have been mixed on whether poor CYP2D6 activity is associated with poorer breast cancer outcomes for people taking tamoxifen—with some studies showing an increased risk of cancer recurrence and others showing no effect.
These mixed findings may be due to the design of previous studies that incompletely characterized the CYP2D6 genotype, according to Matthias Schwab, a clinical pharmacologist and director of the Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology in Stuttgart, Germany, who co-authored an commentary about the meta-analysis but was not involved in the research. Some studies, for example, may misclassify CYP2D6 status because they only factor in a few CYP2D6 variants, he says. In addition, some studies have used DNA collected from patients’ tumors to determine CYP2D6 genotypes, Schwab says. DNA from a person’s tumor often contains genetic changes that are not present in the rest of the body. By contrast, Schwab notes that germline DNA—which a person inherits and is carried in all the body’s cells—could provide a more accurate measure of CYP2D6 activity, especially since tamoxifen is metabolized in the liver.
After the authors of the meta-analysis adjusted for these factors, the difference in the risk of death or recurrence between poor metabolizers and normal metabolizers widened from 28% to 34%.
To Genotype or Not
Schwab, who is a co-author of a Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline that helps clinicians interpret patients’ CYP2D6 genetic test results when prescribing tamoxifen treatment, says he believes people can benefit from CYP2D6 testing if their doctors are considering tamoxifen. The CPIC guideline notes that clinicians can opt for a higher dose of tamoxifen or for another therapy, such as an aromatase inhibitor, if patients have lower CYP2D6 metabolism
However, people with breast cancer do not routinely receive CYP2D6 testing in the U.S., Schwab says. The Food and Drug Administration, which approves drugs in the U.S., and professional organizations, such as the National Comprehensive Cancer Network, do not recommend CYP2D6 testing for patients who are receiving tamoxifen. Insurance companies typically do not cover the costs, he explains.
Hertz does not recommend routine CYP2D6 genotyping for most patients, noting that poor metabolizers make up a minority of the people who receive a breast cancer diagnosis. Globally, about 6% or fewer people have poor metabolizer status. He notes he would use CPIC guidance if patients had already received pharmacogenetic testing and knew their CYP2D6 status.
Maryam Lustberg, a breast medical oncologist at Yale Cancer Center in New Haven, Connecticut, does not recommend CYP2D6 genotyping for her patients receiving tamoxifen, either. “Really, we’ve gotten away from the recommendation of doing any type of genotyping to see if there is variation in enzymatic activity of women taking tamoxifen” due to the inconsistent relationships between CYP2D6 genotype and outcomes observed in different studies, she says.
Lustberg says people with hormone-receptor positive breast cancer would be better served by following the established practices for reducing recurrence risk, including taking hormone therapy consistently and for the duration prescribed. However, Lustberg stresses that patients should make doctors aware of other medications they are taking, since certain antidepressants, such as fluoxetine (Prozac) and paroxetine (Paxil), inhibit CYP2D6 activity and could impair tamoxifen metabolism.
Disclosure: Ashley P. Taylor has previously done some writing for the Yale School of Medicine, which was unrelated to reporting for this article.
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There has been a continuing improvement in breast cancer treatment and extended survival, that is rapidly changing with respect to disease free survival and decreased toxicity. This is a snapshot of recently published work.
1. Breast Cancer Drug Resistance Linked to Gene Family
Two related proteins have been implicated in the mechanisms that allow breast cancer, and potentially other tumor types, to resist therapy with tyrosine kinase inhibitors (TKIs).
Case Western Reserve University
FAM83A and FAM83B have been identified by separate research groups reporting in parallel in the Journal of Clinical Investigation. The proteins may represent promising new therapeutic targets.
Researchers at Case Western Reserve University used a validation-based insertional mutagenesis (VBIM) strategy to generate libraries of HEM1 immortalized human mammary epithelieal cells (HMECs) that carried unique, single genetic alterationsto identify genes that promoted anchorage-independent growth (AIG), and tumorigenicity, and then carried out further cell-based assays to see which of the identified genes could promote tumor growth independently of RAS.
- Expression of FAM83B was found to promote AIG and tumorigenesis, in naïve HME1 cells, and FAM83B-expressing cells were also shown to be capable of forming tumors in immunodeficient mice, confirming its function as a transforming oncogene.
- FAM83B expression levels were associated with specific cancer subtypes, with increased tumor grade, and with decreased overall survival. For example, increased expression of FAM83B was significantly associated with estrogen receptor– (ER-) and progesterone receptor–negative (PR-negative) breast tumors, with higher grade and poor outcome.
- FAM83B also binds with a downstream RAS effector, CRAF, and this binding increased MAPK and mTOR signaling, and reduced sensitivity to EGFR-TKIs.
The Case Western Reserve group concludes that knocking out FAM83B inhibited the proliferation and malignant phenotype of tumor-derived cells or RAS-transformed HMECs.
The authors say targeting FAM38B therapeutically may increase the sensitivity of breast cancer to EGFR-TKI therapy. Given the requirement for FAM83B as an activator of CRAF/MAPK in EGFR and RAS signaling, the levels of FAM83B and FAM83A may be important to consider when determining which patients receive TKI treatment.
MW Jackson., RCipriano, et al. “FAM83B mediates EGFR- and RAS-driven oncogenic transformation.” J Clin Invest 2012.
Lawrence Berkeley National Laboratory-led team
The Berkely group also identified this potential target for addressing drug resistance in breast cancer and potentially other tumor types. The team have reported in the same issue of JCI that a gene known as FAM83A has oncogenic properties, and when overexpressed in cancer cells confers resistance to EGFR-tyrosine kinase inhibitor (EGFR-TKI) drugs and also promotes tumor proliferation and invasion.
- FAM38A had coincidentally previously been identified as highly expressed in lung cancer. The researchers found that, while normal tissue didn’t produce the FAM38A, it was highly expressed in malignant tissue.
- They hypothesized that resistance to EGFR-TKIs may occur in part as a result of a molecular mechanism that triggers phosphorylation signaling downstream of EGFRs.
- They developed a novel three-dimensional cell culture assay based on the phenotypic reversion of malignant cells into phenotypically nonmalignant cells, to screen for genes involved in EGFR-TKI resistance both in normal and cancerous human cell lines.
- FAM83A is expressed in every breast cancer cell line they looked at and was particularly elevated in those that were more resistant to EGFR-TKI treatment.
- FAM38A interacts with and triggers phosphorylation of signaling proteins downstream of EGFR, that act to block the therapeutic effects of EGFR-TKIs.
- When breast cancer cells were treated with an shRNA that blocked FAM38A expression, the cells became less proliferative and more sensitive to EGFR-TKI treatment. Conversely, FAM83A overexpression led to elevated invasiveness.
Mechanistically, FAM83A was shown to interact with and cause phosphorylation of CRAF and PI3K, upstream of MAPK and downstream of EGFR. This finding correlates well with the mechanism reported for FAM38B by the Case Western team.
The published data highlights the potential importance of this family of proteins as potential drug targets, and helps explain existing data demonstrating a clinical correlation between high FAM83A expression and poor cancer prognosis. Moreover, Dr. Bissell states the finding also reveals a whole new family of potential oncogenes that could be a target for all types of cancer, including breast cancer.
Bissell et al. “FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice.” Journal of Clinical Investigation 2012
GEN News Highlights : Sep 12, 2012
2. Targets Identified to Prevent Breast Cancer Spread
Hypoxia-inducible factor 1 (HIF-1) and platelet-derived growth factor B (PDGF-B) may represent promising therapeutic targets for preventing breast cancer from spreading to the lymph nodes and metastasizing to other organs. The protein’s role in lymphatic dissemination of cancer hasn’t been well understood.
Researchers at the Johns Hopkins University School of Medicine and partners in Italy have found that HIF-1 promotes lymphatic metastasis of breast cancer directly by activating the gene encoding PDGF-B, which triggers the growth of new lymphatic vessels.
- Previous work by Gregg L. Semenza, M.D., and colleagues had shown that knocking out HIF-1α or HIF2α in mice implanted with human breast cancer cells (BCCs) slowed tumor growth and lung metastasis.
- Treating animals with the HIF-1 inhibitor digoxin similarly impaired primary tumor growth and lung metastasis.
- Mice injected with HIF-1 knockdown human BCC cells exhibited 76% fewer cancer cells in their lymph nodes after 24 days than animals injected with unengineered BCC cells, supporting a role for HIF-1 in the spread of breast cancer to lymph nodes.
- HIF-1 binds directly to the gene for PDGF-B, which is overexpressed under the hypoxic conditions found in tumors, and triggers the growth of lymphatic vessels.
- Moreover, coexpression of HIF-1α and PDGF-B was also found in invasive breast carcinomas, and this coexpression correlated with survival and response to chemotherapy, the researchers stress.
- PDGF-B produced as a result of HIF-1 binding is released from the tumor cells and binds to its cognate receptor PDGFRβ, which is upregulated on lymphatic endothelial cells (LEC) under hypoxic conditions.
- This PDGFβ signaling triggers LEC proliferation and migration, and the growth of lymphatic vessels.
- When the researchers turned off PDGFRβ signalling by blocking HIF-1 or PDGF-B using either RNA interference, or chemical inhibitors (digoxin or the tyrosine kinase inhibitor imatinib), both lymphatic vessel density and lymph node metastasis were significantly reduced.
Reporting their findings in PNAS, the investigators suggest:
highlighting HIF-1 and PDGF-B as potential therapeutic targets for breast cancer their results suggest that co-expression of the two proteins may help to identify lymph node-negative patients who are at a high risk for developing lymph node metastasis
GL Semenza, et al. “Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells.” PNAS 2012.
GEN News Highlights : Sep 12, 2012
3. how tamoxifen-resistant breast-cancer cells grow and proliferate
A study by researchers at the Ohio State University Comprehensive Cancer Center (OSUCCC – James) has discovered how tamoxifen-resistant breast-cancer cells grow and proliferate.
It suggests that an experimental agent might offer a novel targeted therapy for tamoxifen-resistant breast cancer.
- Like a second door that opens after the first door closes, a signaling pathway called hedgehog (Hhg) can promote the growth of breast-cancer cells after tamoxifen shuts down the pathway activated by the hormone estrogen.
- A second signaling pathway, called PI3K/AKT, is also involved. Activation of the Hhg pathway renders tamoxifen treatment ineffective and enables the tumor to resume its growth and progression.
- The researchers found that the tumors with an activated Hhg pathway had a worse prognosis.
- an experimental drug called vismodegib, which blocks the Hhg pathway, inhibits the growth of tamoxifen-resistant human breast tumors in an animal model. The drug is in clinical trials testing for other types of cancer.
This study has identified targeted therapies that could be an alternative to chemotherapy for these resistant tumors. The study is published in the journal Cancer Research 2012.
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Possible therapy for tamoxifen-resistant breast cancer identified cphi-online.com
EGF Signalling (Photo credit: TheJCB)
Related articles
- How breast cancer spreads (eurekalert.org)
- How breast cancer spreads: Researchers find key to lymph node metastasis in mice (medicalxpress.com)
- PARP inhibitors may have clinical utility in HER2-positive breast cancers (eurekalert.org)
- Lack of oxygen in cancer cells leads to growth and metastasis (eurekalert.org)
- Protein Linked To Therapy Resistance In Breast Cancer (medicalnewstoday.com)
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
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