Discovery of new mechanism of resistance to endocrine or anti-hormonal therapies

Aug 13 2007

When a woman receives a breast cancer diagnosis her entire life may change in the blink of an eye.

But the nature of that change is governed by the smallest alterations that take place within the proteins of the tumor cells, determining what treatments she can pursue with a hope of cure and those to which her cancer is resistant.

Scientists from the Lombardi Comprehensive Cancer Center have announced the discovery of a new mechanism of resistance to endocrine or anti-hormonal therapies, such as Tamoxifen and Faslodex. This research may allow oncologists to screen women for responsiveness to these treatments, and provides a much-needed clue to reversing resistance. The research, led by Robert Clarke, PhD, DSc, a professor of oncology and of physiology and biophysics at Georgetown University Medical Center, indicates that a gene previously thought to be unrelated to breast cancer may be responsible for some resistance to endocrine therapy.

The gene, called human X-box binding protein-1 (XBP1), is an alternatively spliced transcription factor that participates in a stress-signaling pathway to protect cells from damage. In a paper published online in the Journal of the Federation of American Societies for Experimental Biology (FASEBJ) on July 27, Clarke and his colleagues at the Lombardi Comprehensive Cancer Center (part of Georgetown University Medical Center) found that over-expression of the spliced variant of the gene in estrogen receptor-positive breast cancer cells led to reduced sensitivity to Tamoxifen and Faslodex.

According to Lombardi medical oncologist Minetta Liu, MD, it is expected that all hormone receptor positive metastatic breast cancers will eventually develop resistance to endocrine therapies. When this happens, doctors must switch their patients to a different class of drugs , throwing their lives into limbo once again as treatment schedules are changed and new side effects develop.

"When cell lines changed from being sensitive to endocrine therapy to being resistant, we saw an increase in spliced XBP1 inside the cell. So then we took sensitive cells and added spliced XBP1, which made them resistant to the therapy," explained Clarke, who is interim director of Georgetown's Biomedical Graduate Research Organization and co-leader of the Breast Cancer Program at the Lombardi Comprehensive Cancer Center.

Anti-hormonal therapies are some of the most effective treatments for breast cancer because estrogen, a natural female sex hormone, can drive the growth of the tumor. Tamoxifen and other anti-hormonal therapies cut off the tumor's access to estrogen, causing the tumor to stabilize and sometimes even shrink. However according to Clarke, many cancers become insensitive to these treatments over time , more than half of all recurring breast cancers lose sensitivity , because they have found a way to keep growing in the absence of estrogen.

Previously, Clarke and his team found that XBP1 is co-expressed with the estrogen receptor in breast tumor cells. This may mean that the effects of XBP1 over-expression occur when the protein is bound to the estrogen receptor, suggesting for the first time that these two proteins interact in the cell. This was the first evidence that the XBP1 protein may play a role in breast cancer pathways.

Through molecular profiling of the downstream effects of the spliced XBP1, Dr. Clarke and his colleagues discovered that expression of several anti-apoptotic genes responsible for programmed cell death , including BCL2 , are altered. While they have not yet determined the exact interactions that take place, the researchers believe that the overexpression of XBP1 promotes cell survival by affecting the activity of the intrinsic apoptosis pathway.

"XBP1 may give us a much-needed clue for better predicting response to anti-estrogen therapies like Tamoxifen," explained Clarke. "The presence of the activated protein at high levels should predict estrogen independence and thus resistance to these therapies."

In the future, Clarke also hopes to develop a new therapeutic treatment based on this discovery. He believes that the XBP1 pathway can be targeted in patients receiving treatment to ensure their tumors do not become resistant to the anti-hormonal therapies. Using this discovery, Clarke also hopes to find a way to reverse resistance to anti-hormonal therapies, making it possible for women to continue treatment with first line therapies for longer.

However, Clarke said that the next step in this research will be to conduct a trial to test the predictive power of XBP1 in the clinic.