Researchers Identify Genes that Render Breast Cancer Resistant to Tamoxifen

Researchers Identify Genes that Render Breast Cancer Resistant to Tamoxifen

Most incurable breast cancers occur in women with recurrent, estrogen receptor (ER)-positive, metastatic tumors, so there is a critical need for therapeutic approaches that include novel, targeted strategies by which ER-positive tumors can be resensitized to endocrine therapies.

Now, a team of researchers led by Zeynep Madak-Erdogan at the University of Illinois may have discovered the genetic code that determines why many patients with this aggressive cancer fail to respond to tamoxifen, the most commonly used drug for this type of breast cancer.

The study, “ERα-XPO1 crosstalk controls tamoxifen sensitivity in tumors by altering ERK5 cellular localization, was published in the journal Molecular Endocrinology.

According to the study’s results, patients with higher levels of certain nuclear transport genes, particularly the protein XPO1, have poor survival rates and are more likely to be resistant to tamoxifen.

However, the researchers found that the use of tamoxifen in combination with selinexor, an experimental drug that restrains the activity of the XPO1 protein, enhances patients’ sensitivity to tamoxifen and prevents breast cancer recurrence.

In their experiments, the team also identified a “signature” of 13 nuclear transport genes, including XPO1, which may offer clinicians a biomarker to predict which patients may be endocrine-resistant, thereby selecting other treatment options for these patients.

Estrogen receptor alpha (ERα) accounts for about 70 percent of human breast cancers and is considered one of the most critical predictive factors of breast cancer prognosis. ERα is targeted by endocrine therapies, which are generally well-tolerated. Tamoxifen is one of the most effective therapeutics when a patient is diagnosed with ERα-positive breast cancer. But about one-third of patients with this aggressive breast cancer do not respond adequately or eventually fail to respond to tamoxifen, a condition called endocrine resistance.

When compared with other endocrine-targeting agents, tamoxifen is still considered a very effective treatment. But determining which patients will effectively respond to the drug remains a challenge to both the scientific and medical community.

The new study was conducted based on previous research by University of Illinois scientists, who were able to identify the hormone estrogen as the agent responsible for the activation and regulation of the protein kinase ERK5, which sends signals from outside cells to their nuclei, thus causing either increased cell proliferation or metastasis.

In the current study, researchers theorized that nuclear transport genes, mainly XPO1, could be involved in exporting ERK5 from cells’ nuclei, stimulating aggressive tumors.

The team used advanced statistical methods that included meta-analyses of breast tumors’ genetic data, monitoring gene expression using human breast cancer cells, and experiments using ERα-positive breast cancer mouse models.

In their analysis of the genes that were differentially expressed in ERα-positive and ERα-negative breast tumors, the scientists were able to identify 13 genes that were over-expressed in the more invasive breast cancers.

“When we looked into the gene signature further, we found that if a patient had higher expression of XPO1, their survival time was less, they had metastases earlier on, and endocrine-resistant tumor cells proliferated more rapidly when treated with tamoxifen,” Madak-Erdogan said in a news release.

In their experiments, the scientists mimicked endocrine resistance by cultivating tamoxifen-responsive breast cancer cells derived from 33 patients in a tamoxifen solution for a period of 100 weeks. They then studied ERK5’s activity at three different intervals, and discovered that the transportation of ERK5 to the cells’ nuclei progressively declined as the endocrine resistance advanced.

The researchers then postulated that a combined treatment approach could help restore endocrine sensitivity. In their experiments, they treated mice with tamoxifen-resistant breast cancer cells with increasing doses of selinexor in combination with tamoxifen.

“When we treated those tamoxifen-resistant tumors with the inhibitor for XPO1 in combination with tamoxifen, we were able to completely block tumor progression,” Madak-Erdogan said. “Even weeks after the treatment was done, we didn’t see any tumor recurrence.”

“If we use this combination — targeting the estrogen receptors with tamoxifen, and XPO1 with the inhibitor selinexor — we can delay the development of endocrine resistance, effectively killing the tumor cells and at the same time reducing the dose of tamoxifen that’s needed,” said Madak-Erdogan, who also holds a position in the Division of Nutritional Sciences.