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.