Tamoxifen (Soltamox/Nolvadex?; AstraZeneca), an antagonist of the estrogen receptor ? in ER?-positive breast cancer has been effective in most patients. The drug has been used for more than 40 years to treat breast cancers that are hormone-receptor positive. As an adjuvant therapy tamoxifen improves overall survival. Its widespread use is thought to have made a significant contribution to the reduction in breast cancer mortality seen over the last decade. [1] However, resistance to tamoxifen is a clinically significant problem.

So far, the mechanisms responsible for tamoxifen resistance remain elusive. Results from a study funded by the Dutch Cancer Society(KWF) published in Cancer Research, a journal of the American Association for Cancer Research discusses a new approach that has the potential to be used in the clinic to predict which patients with estrogen receptor-positive breast cancer will benefit from tamoxifen therapy after surgery.[2]

?We have used a very innovative approach to identify genes that help foretell whether a patient will respond to tamoxifen, and we showed that this gene signature performed well in two large patient groups,? explained Ren? Bernards, PhD, professor and head of the Division of Molecular Carcinogenesis at the Netherlands Cancer Institute (NKI) in Amsterdam, The Netherlands.

… the researchers identified a gene called USP9X, whose loss of function in breast cancer cells resulted in tamoxifen resistance…

Relapse after adjuvant treatment
?About one-third of women with hormone receptor-positive breast cancer experience a relapse after adjuvant treatment with tamoxifen. Median overall survival in these patients, even with further treatment, is around 30 to 45 months,? Bernards explained. ?It has been very difficult to identify patients whose tumors lack a proper response to tamoxifen, the most frequently used drug in breast cancer.

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Bernards and his team performed a large scale loss-of-function genetic screen in ZR-75-1 luminal breast cancer cells and found that loss of function in the deubiquitinase USP9X prevented proliferation arrest by tamoxifen, but not by the ER downregulator fulvestrant (Faslodex?; MedImmune/AstraZeneca). [2]

?By using CHIPseq and RNAseq technologies in combination with RNA expression data from publically available data sets, we were able to translate results from cell culture experiments into a diagnostic tool that has the potential to help identify breast cancer patients that will benefit from tamoxifen,? Bernards added.

Knockdown ofUSP9Xincreases ER? activity
To find out whether loss of function of certain genes is involved in resistance to tamoxifen, Bernards and his colleagues took human hormone receptor-positive breast cancer cells and infected them with thousands of small pieces of RNA called shRNAs, each designed to silence a specific gene. TheshRNA screen singled out a geneinvolved in tamoxifen resistance.By studying the shRNAs that survived despite treatment with tamoxifen, the researchers identified a gene called USP9X, whose loss of function in breast cancer cells resulted in tamoxifen resistance.

Altered after Tamoxifen
Next, the researchers identified other genes that were altered during treatment with tamoxifen, in the absence of USP9X. Then, using publicly available data sets, they studied the expression of these specific genes in patients who were treated with tamoxifen after surgery, and whose treatment outcomes were known. They found that the data split into two groups, one with a gene signature with a good outcome, and the other with a signature showing bad outcome, after treatment with tamoxifen.

The gene signature they identified could not predict treatment outcomes in patients who did not receive tamoxifen therapy, suggesting that this signature is specific to outcomes with tamoxifen treatment.

Different data sets
Collectively, the researchers used data from about 680 patients from four different data sets to test the utility of the gene signature in predicting responses to tamoxifen therapy in hormone receptor-positive breast cancer patients.

?We are currently validating our promising results using the data from a prospective randomized controlled trial, and we expect to complete this validation by the end of this year,? said Bernards. ?If this is successful, clinical implementation is a logical next step.?

For more information:
[1] Ring A, Dowsett M. Mechanisms of tamoxifen resistance. Endocr Relat Cancer. 2004 Dec;11(4):643-58. [Article][PubMed]
[2]Oosterkamp HM, Hijmans EM, Brummelkamp TR, Canisius S, Wessels LF, Zwart W, Bernards R. USP9X Downregulation Renders Breast Cancer Cells Resistant to Tamoxifen. Cancer Res. 2014 Jul 15;74(14):3810-20. doi: 10.1158/0008-5472.CAN-13-1960. [Article][PubMed]

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