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Researchers Identify New Pathway, Enhancing Tamoxifen to Tame Aggressive Breast Cancer
By Dross at 2013-04-24 23:48
Researchers Identify New Pathway, Enhancing Tamoxifen to Tame Aggressive Breast Cancer

Tamoxifen is a time-honored breast cancer drug used to treat millions of women with early-stage and less-aggressive disease, and now a University of Rochester Medical Center team has shown how to exploit tamoxifen’s secondary activities so that it might work on more aggressive breast cancer.

The research, published in the journal EMBO Molecular Medicine, is a promising development for women with basal-like breast cancer, sometimes known as triple-negative disease. This subtype has a poor prognosis because it is notoriously resistant to treatment. In fact, basal-like cancers lack the three most common breast cancer biomarkers – the estrogen receptor, the progesterone receptor, and theHer2/neu receptor – and without these receptors, the usual front-line treatments are not effective.

Until recently, tamoxifen was known primarily for its ability to block estrogen receptors on the outside of cancer cells. However, new studies have suggested that when tamoxifen is given in higher doses, it works through a second mechanism of action independent of the estrogen receptor. This second mechanism was the focus of the Rochester laboratory.

Led by doctoral student Hsing-Yu Chen and Mark Noble, Ph.D., professor of Biomedical Genetics at URMC, the team studied the molecular mechanism that allows basal-like breast cancer cells to escape the secondary effects of tamoxifen, and discovered that two proteins are critical in this escape. One protein, called c-Cbl, controls the levels of multiple receptors that are critical for cancer cell function. A second protein, Cdc42, can inhibit c-Cbl and is responsible for the tumor’s underlying resistance.

The team also discovered that targeting Cdc42 – and thus inhibiting the inhibitor - with an experimental drug compound known as ML141 restored c-Cbl’s normal function. Through additional work in animal models and in human cell cultures, the team demonstrated that when ML141 is paired with tamoxifen, it enhances the ability of tamoxifen to induce cancer cell death and suppress the growth of new cancer cells. Neither drug alone had the same effect on basal-like breast cells.

Noble believes there is considerable value to targeting Cdc42, because elevated levels of the protein have been observed in multiple types of cancer. (In this context, scientists are also studying the potential for tamoxifen as a therapy for other cancers.)

The powerful ML141-tamoxifen drug combination looks like it has two more important features: It selectively targets cancer cells while sparing normal, healthy cells; and it appears to cripple cancer stem cells, the primitive cells responsible for initiating new tumors and for fueling the bulk of the tumor cell population.  

 “Our work is very exciting because our approach simultaneously addresses two of the most critical challenges in cancer research -- to increase the utility of existing therapies and to discover new vulnerabilities of cancer cells,” said Noble, who also is a leader at UR’s Stem Cell and Regenerative Medicine Institute. “Based on these discoveries, we are already pushing forward with new compounds and with new approaches that might make clinical translation of this discovery much more rapid than would occur with traditional drug-discovery approaches.”

The National Institutes of Health, Susan G. Komen for the Cure, the U.S. Department of Defense, and the New York State NYSTEM initiative funded the research. Co-authors include Yin Miranda Yang, Ph.D., and Brett Stevens, Ph.D.

Hsing-Yu Chen won a Howard Hughes Medical Institute Award of Excellence in 2012 for a poster presentation on this topic.



1 comment | 4009 reads

by gdpawel on Thu, 2013-04-25 12:54
Researchers at Karolinska Institutet in Sweden have developed a method for assessing the effect of tamoxifen, a common drug to prevent the relapse of breast cancer. The key lies in monitoring changes in the proportion of dense tissue, which appears white on a mammogram, during treatment. Women who show a pronounced reduction in breast density during tamoxifen treatment have a fifty per cent reduction in breast cancer mortality. This tool provides doctors with the possibility to assess whether a patient is responding to tamoxifen at an early phase of treatment.

Tamoxifen is a common hormone therapy drug that is usually given over a course of five years to prevent relapse in women who have completed their primary breast cancer treatment. However, no method has been available for assessing which women are likely to respond to the tamoxifen and not develop relapse of breast cancer. Researchers from Karolinska Institutet have now produced a possible way of doing just this.

The team looked into mammograms, which are X-ray images of the breast, for an answer. Breast tissue on a mammogram can be broadly classified into fatty or dense. The proportion of tissue which appears white is what contributes to 'density', whilst the black parts are mostly fat. Since tamoxifen has been repeatedly shown to induce a reduction in mammographic density, could it be that only women responding to tamoxifen treatment would exhibit a concomitant decrease in mammographic density?

The study included almost 1,000 postmenopausal women who had been treated for breast cancer. Roughly half of the group had been given tamoxifen. The women were monitored over an average of 15 years, after which 12.4 per cent (121 women) had died as a result of their cancer.

The team discovered that the difference in mammographic density between two mammograms taken after the initiation of tamoxifen was related to breast cancer survival. Women who experienced a pronounced density reduction of 20 percent or more upon initiation of tamoxifen were half as likely to die from breast cancer, over a span of 15 years, than those who experienced little or no change.

The researchers hope that their results will be used to assess which breast cancer patients are responding to tamoxifen treatment. Since the patient group already undergoes annual follow-up mammograms, no further examinations are needed.

"What's needed is accurate measurement of mammographic density, which isn't currently routine," says Per Hall, Professor at Karolinska Institutet's Department of Medical Epidemiology and Biostatistics. "Measuring changes in density can be a simple and cheap means of assessing the effect of the treatment. If a patient is not responding to tamoxifen, maybe they should be given a different drug."

The study was financed with grants from the Märit and Hans Rausing Initiative Against Breast Cancer, and the Swedish Cancer Society.

Reference: “Mammographic Density Reduction Is a Prognostic Marker of Response to Adjuvant Tamoxifen Therapy in Postmenopausal Patients With Breast Cancer,” Jingmei Li, Keith Humphreys, Louise Eriksson, Gustaf Edgren, Kamila Czene, and Per Hall. Journal of Clinical Oncology, online 22 April 2013, doi;10.1200/JCO.2012.44.5015.

Citation: Journal of Clinical Oncology. "Mammograms Reveal Response To Common Cancer Drug." Medical News Today. MediLexicon, Intl., 24 Apr. 2013.

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