Breast cancer drug fulvestrant appears more effective in the presence of CK8 and CK18
Women's responsiveness to the second-line breast cancer drug fulvestrant may depend on whether the cancer cells are expressing two key proteins, Indiana University Bloomington scientists report in this month's Cancer Biology & Therapy.
Fulvestrant appeared to exert maximum anti-cancer effects in vitro when cells produced normal or elevated quantities of the cytokeratins CK8 and CK18, structural proteins that help give the nucleus its shape.
Image by Kenneth Nephew
The figures show that fulvestrant-mediated cytoplasmic localization of ER is associated with intermediate filament proteins CK8 and CK18. After treatment of MCF-7 and T47D cells (breast cancer cells) with Fulvestrant, dramatic cytoplasmic localization of ER was observed. The results indicate that the presence of CK8 and CK18 is necessary for fulvestrant-induced cytoplasmic localization of ER, which keeps the receptor away from the nucleus where it could activate growth promoting genes.
For fulvestrant to work well, the cells must also be responsive to estrogen, and producing the estrogen receptor ER-alpha. ER-alpha's importance to fulvestrant's anti-estrogenic action had been established in previous reports. The present study confirms fulvestrant's binding relationship to ER-alpha, while also showing two other proteins, cytokeratins 8 and 18, can strongly enhance fulvestrant's anti-estrogenic activity. Testing for the presence of these three proteins, and perhaps many others, could help doctors decide whether fulvestrant should be prescribed to their patients.
"We need an effective panel of markers that inform physicians about what treatment options will be most beneficial to patients," said Medical Sciences Program Bloomington cancer biologist Kenneth Nephew, who led the study. "These three gene products should be investigated further to determine whether they should be included in that panel."
Medical Sciences Program Bloomington is a division of the IU School of Medicine. Nephew is a professor of cellular and integrative physiology, and obstetrics and gynecology.
"Normal" breast cancer cells can grow faster in the presence of estrogen, a hormone. Estrogen attaches to receptors embedded in the cancer cell, such as ER-alpha in the cytoplasm and nucleus. The estrogen-ER complex can then act to turn on genes or amplify their expression. Not all cancer cells are responsive to estrogen, however, or to fulvestrant, which counteracts estrogen's effects.
Although fulvestrant has been used to treat cancer since the late 1980s, and is now commonly prescribed as a second-line defense against metastatic cancer cells, how the drug works is still not completely understood. Nephew said one of the aims of the research is to clarify fulvestrant's biochemistry, and understand why cancer cells eventually become unresponsive to the drug.
Second-line breast cancer therapies are employed when first-line approaches (tamoxifen, for example) don't work or stop working.
This article was originally published on March 10, 2010.
