Nguyen
10-02-2008, 09:50 AM
http://cancerres.aacrjournals.org/cgi/content/full/68/12/4518 (http://cancerres.aacrjournals.org/cgi/content/full/68/12/4518)
Using the intratumoral aromatase xenograft model, we have observed<SUP> </SUP>that despite long-lasting growth inhibition, tumors eventually<SUP> </SUP>begin to grow during continued letrozole treatment. In cells<SUP> </SUP>isolated from these long-term letrozole-treated tumors (LTLT-Ca),<SUP> </SUP>estrogen receptor-http://cancerres.aacrjournals.org/math/alpha.gif (ERhttp://cancerres.aacrjournals.org/math/alpha.gif) levels were decreased, whereas signaling<SUP> </SUP>proteins in the mitogen-activated protein kinase cascade were<SUP> </SUP>up-regulated along with human epidermal growth factor receptor<SUP> </SUP>2 (Her-2). In the current study, we evaluated the effect of<SUP> </SUP>discontinuing letrozole treatment on the growth of letrozole-resistant<SUP> </SUP>cells and tumors. The cells formed tumors equally well in the<SUP> </SUP>absence or presence of letrozole and had similar growth rates.<SUP> </SUP>After treatment was discontinued for 6 weeks, letrozole was<SUP> </SUP>administered again. Marked tumor regression was observed with<SUP> </SUP>this second course of letrozole treatment. Similarly, in MCF-7Ca<SUP> </SUP>xenografts, a 6-week break in letrozole treatment prolonged<SUP> </SUP>the responsiveness of the tumors to letrozole. To understand<SUP> </SUP>the mechanisms of this effect, LTLT-Ca cells were cultured in<SUP> </SUP>the absence of letrozole for 16 weeks. The resulting cell line<SUP> </SUP>(RLT-Ca) exhibited properties similar to MCF-7Ca cells. The<SUP> </SUP>cell growth was inhibited by letrozole and stimulated by estradiol.<SUP> </SUP>The expression of phosphorylated mitogen-activated protein kinase<SUP> </SUP>(MAPK) was reduced and ERhttp://cancerres.aacrjournals.org/math/alpha.gif and aromatase levels increased compared<SUP> </SUP>with LTLT-Ca cells and were similar to levels in MCF-7Ca cells.<SUP> </SUP>These results indicate that discontinuing treatment can reverse<SUP> </SUP>letrozole resistance. This could be a beneficial strategy to<SUP> </SUP>prolong responsiveness to aromatase inhibitors for patients<SUP> </SUP>with breast cancer. [Cancer Res 2008;68(12):4518–24]<SUP> </SUP>
Using the intratumoral aromatase xenograft model, we have observed<SUP> </SUP>that despite long-lasting growth inhibition, tumors eventually<SUP> </SUP>begin to grow during continued letrozole treatment. In cells<SUP> </SUP>isolated from these long-term letrozole-treated tumors (LTLT-Ca),<SUP> </SUP>estrogen receptor-http://cancerres.aacrjournals.org/math/alpha.gif (ERhttp://cancerres.aacrjournals.org/math/alpha.gif) levels were decreased, whereas signaling<SUP> </SUP>proteins in the mitogen-activated protein kinase cascade were<SUP> </SUP>up-regulated along with human epidermal growth factor receptor<SUP> </SUP>2 (Her-2). In the current study, we evaluated the effect of<SUP> </SUP>discontinuing letrozole treatment on the growth of letrozole-resistant<SUP> </SUP>cells and tumors. The cells formed tumors equally well in the<SUP> </SUP>absence or presence of letrozole and had similar growth rates.<SUP> </SUP>After treatment was discontinued for 6 weeks, letrozole was<SUP> </SUP>administered again. Marked tumor regression was observed with<SUP> </SUP>this second course of letrozole treatment. Similarly, in MCF-7Ca<SUP> </SUP>xenografts, a 6-week break in letrozole treatment prolonged<SUP> </SUP>the responsiveness of the tumors to letrozole. To understand<SUP> </SUP>the mechanisms of this effect, LTLT-Ca cells were cultured in<SUP> </SUP>the absence of letrozole for 16 weeks. The resulting cell line<SUP> </SUP>(RLT-Ca) exhibited properties similar to MCF-7Ca cells. The<SUP> </SUP>cell growth was inhibited by letrozole and stimulated by estradiol.<SUP> </SUP>The expression of phosphorylated mitogen-activated protein kinase<SUP> </SUP>(MAPK) was reduced and ERhttp://cancerres.aacrjournals.org/math/alpha.gif and aromatase levels increased compared<SUP> </SUP>with LTLT-Ca cells and were similar to levels in MCF-7Ca cells.<SUP> </SUP>These results indicate that discontinuing treatment can reverse<SUP> </SUP>letrozole resistance. This could be a beneficial strategy to<SUP> </SUP>prolong responsiveness to aromatase inhibitors for patients<SUP> </SUP>with breast cancer. [Cancer Res 2008;68(12):4518–24]<SUP> </SUP>