Genes Responsible for Tamoxifen Resistance in Breast Cancer Identified

Roxanne Nelson

April 14, 2008

April 14, 2008 (San Diego, California) — Although endocrine therapy has proven to be highly effective in the treatment of breast cancer, resistance to therapeutic agents frequently develops over time. However, a set of 7 genes has been identified that might be responsible for drug resistance and tumor aggressiveness, researchers report at the American Association for Cancer Research (AACR) 2008 Annual Meeting.

The genes appear to be of clinical relevance, and because they offer insight into both the molecular and cellular pathways of breast tumor aggressiveness and tamoxifen resistance, their identification might provide novel targets for preventive approaches and personalized treatment strategies.

"Our work should be placed in the context that 40,000 women in the United States still die yearly of the disease, and we don't know enough about why treatment fails or why the disease recurs," said senior author Lambert C.J. Dorssers, PhD, a cell biologist from the department of pathology at Erasmus MC University Medical Center, in Rotterdam, the Netherlands. "More information is needed."

Hormone therapy such as tamoxifen has become a very important treatment option for breast cancer patients, because the majority of breast cancers are dependent on steroid hormones. "But in due course, all tumors will become resistant to these drugs and will continue to grow," Dr. Dorssers told journalists. "This will ultimately be fatal to patients. There is an urgent need to know how tumors evade therapy and how they become resistant."

The majority of breast cancers are estrogen-receptor positive (ER+), and a large proportion of patients with ER+ cancer will respond to anti-estrogen therapy, such as tamoxifen. Approximately half of all patients with advanced breast cancer will experience a clinical benefit from tamoxifen treatment, but the disease will usually evolve into a resistant phenotype.

"In our study, we searched for genes that allow tamoxifen to become resistant," Dr. Dorssers told journalists. "The characteristics of these genes reveal that there are different ways that the genes can become resistant."

The underlying molecular basis of the failure of endocrine therapy is not understood at this time. Although gene expression profiling research has been able to provide insight by identifying patients who are most likely to benefit from a specific intervention, these genes generally do not define the underlying molecular mechanisms.

Dr. Dorssers and colleagues hypothesized that cell proliferation in the absence of estrogen and in the presence of tamoxifen would be regulated at a molecular level by specific genes. They used a functional screen to identify what they termed "breast cancer anti-estrogen resistance" (BCAR) genes, and evaluated their role in a large breast cancer cohort.

They subjected estrogen-dependent ZR-75 human breast cancer cells to insertion mutagenesis with replication-defective retroviruses, which were then selected to propagate in the presence of 4-hydroxy tamoxifen. The researchers ultimately identified 7 BCAR genes (AKT1, AKT2, BCAR1, BCAR3, EGFR, GRB7, and TRERF1) that caused the tamoxifen-resistant phenotype.

"Some of the genes we found were already known to be important in the resistance of breast tumors to tamoxifen," said Dr. Dorssers. "In general, the genes that are on our list play a powerful role in cell growth and activate an evasive mechanism that allows them to grow."

To determine the clinical relevance of these genes, 561 ER+ primary breast cancers were evaluated for tumor aggressiveness and resistance to tamoxifen therapy. The end point for tumor aggressiveness was metastasis-free survival among patients with lymph-node-negative disease.

The researchers evaluated resistance to therapy in a patient cohort that received tamoxifen as first-line therapy for recurrent disease; the end point for this part of the analysis was progression-free survival.

Metastasis-free survival was statistically associated with AKT2, EGFR, TLE3, and TRERF1 mRNA levels, and multivariate analyses that included traditional prognostic factors showed AKT2, EGFR, and TRERF1 to be independent prognostic factors. AKT2, EGFR, and TRERF1 were also associated with tumor aggressiveness.

For the end point of progression-free survival, the mRNA levels of BCAR3, ERBB2, GRB7, TLE3, and TRERF1 were independently associated with the duration of clinical benefit of tamoxifen therapy.

There are many unanswered questions, commented William N. Hait, MD, PhD, senior vice president and worldwide head of Ortho Biotech Oncology Research and Development and president of AACR for the 2007/08 term. "Only about 50% of women who express the hormone receptor respond to hormone therapy, so why doesn't the other half respond? The second question is why, essentially, does every woman who gets hormone therapy and lives long enough eventually become resistant to the therapy?"

"This is a huge problem," he added, "Because unfortunately, when breast cancer recurs, the prognosis is very bleak. The importance of this research is enormous."

The study was supported by the Dutch Cancer Society, the Susan G Komen Breast Cancer Foundation, and the Association for International Cancer Research.

American Association for Cancer Research (AACR) 2008 Annual Meeting: Abstract 1582. Presented April 13, 2008.


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