A US study found a new way in which breast cancer becomes resistant to tamoxifen, the most widely sold drug for breast cancer prevention and treatment throughout the world. The researchers suggest this could be an early way to spot patients who are not responding to tamoxifen and give doctors time to find an alternative treatment sooner.
The study was the work of researchers based at the Georgetown University School of Medicine, in Washington, District of Columbia, and other research centres in the US and is published in the 1 November issue of the journal Cancer Research.
Tamoxifen is used to treat early and advanced estrogen receptor positive breast cancer in pre and post-menopausal women and is also used to prevent breast cancer in women at high risk of developing it.
Tamoxifen is a selective estrogen receptor modulator (SERM) that binds to particular estrogen receptors on breast cancer cells and stops them dividing.
Lead author Dr Rebecca Riggins, a a research assistant professor of oncology at the Lombardi Comprehensive Cancer Center in the Georgetown University School of Medicine, and colleagues discovered that breast cancer cells that are resistant to tamoxifen have fewer of the “alpha” estrogen receptors that the drug binds to and more of the “gamma” estrogen-related receptors that the drug appears to stimulate.
They found that as resistance grows, the breast cancer cells gradually lose alpha receptors and gain more gamma receptors.
The study has shed new light on the differences between the alpha and the gamma receptors. They are not close relatives: they are more like cousins than siblings said the researchers. And, as Riggins explained, the study has also helped to understand the important role of the gamma estrogen-related receptor in breast cancer:
“Until now, this receptor has not been viewed to be of much importance in any type of breast cancer,” said Riggins.
“All that was known is that there were more of these receptors in breast cancer than in normal breast tissue, we hadn’t gone much further than that,” she added.
The discovery may also explain why invasive lobular carcinoma, the type of breast cancer examined in this study, does not respond as well to tamoxifen as other types of breast cancer. Riggins said because it was not clear whether tamoxifen was effective for invasive lobular carcinoma (compared to another subtype like invasive ductal carcinoma for instance), it has been a debating point among clinicians.
“This study is a good first step toward clarifying the role that tamoxifen resistance apparently plays in treatment of invasive lobular cancer,” she explained.
For the study the investigators first cultured some tamoxifen-resistant invasive lobular carcinoma cells by taking cells of the subtype and exposing them to low amounts of the drug and then letting them adapt to it. Then they slowly increased the concentration of the drug to match the dose that a woman undergoing treatment would be exposed to for 10 months and monitored how the cells’ resistance increased.
“Initially the cells were sensitive to tamoxifen, but as the dose increased, the sensitive cells died off, and the tumor repopulated itself with resistant cells,” explained Riggins.
As they monitored the cells, the investigatos also measure gene expression and found expression of the gamma estrogen-related receptor subtype increased over time. Riggins said it was clear that:
“The gamma estrogen-related receptors, which have a role in cell metabolism, are stimulating cancer growth, and it is possible that tamoxifen is activating this receptor.”
About 15 per cent of new breast cancers diagnosed every year are of the invasive lobular carcinoma subtype, whose tumors under the microscope look long and thin. They actually comprise strings of individual cancer cells lined up next to each other. This makes the cancer subtype harder to diagnose than ones where the cells form clumps as in invasive ductal carcinoma.
The researchers are excited because although strictly speaking their findings are limited to the type of cancer they examined, the invasive lobular carcinoma subtype, the results may also explain why tamoxifen resistance develops during the treatment of other subtypes: they could also be increasing the gamma estrogen-related receptors and decreasing the alpha ones.
“No one has looked for gamma estrogen-related receptors in tamoxifen resistance in invasive ductal carcinoma,” said Riggins.
The impact of this discovery is not to be underestimated said Riggins.
“More than 178,000 women will be diagnosed this year with invasive breast cancer, and 70 percent of them will have estrogen receptor-positive tumors,” she explained, adding that “it is clear that we need to understand why this resistance occurs.”
Senior investigator Dr Robert Clarke, who is professor of oncology, physiology and biophysics and director of the Biomedical Graduate Research Organization at the Georgetown University School of Medicine said:
“This is a very nice story of tamoxifen resistance in a somewhat under-investigated group of breast cancers.”
He said the study has found a “new player” and how its signalling affects how tamoxifen responds in these breast cancers.
Perhaps there is scope for a new drug to target the gamma estrogen-related receptors, in the same way that tamoxifen targets the alpha ones. That’s another reason to be excited by these findings.
“ERR{gamma} Mediates Tamoxifen Resistance in Novel Models of Invasive Lobular Breast Cancer.”
Rebecca B. Riggins, Jennifer P-J. Lan, Uwe Klimach, Alan Zwart, Luciane R. Cavalli, Bassem R. Haddad, Li Chen, Ting Gong, Jianhua Xuan, Stephen P. Ethier, and Robert Clarke.
Cancer Res 2008 68: 8908-8917.
doi: 10.1158/0008-5472.CAN-08-2669
Sources: Georgetown University Medical Center.
Written by: Catharine Paddock, PhD.