The Akt
kinase is a
serine/threonine protein kinase that has been implicated in mediating a variety of
biological responses. Studies show that high Akt activity in
breast carcinoma is associated with a poor pathophenotype, as well as
hormone and
chemotherapy resistance. Additionally, high Akt activity is associated with other features of poor prognosis. Thus, a chemotherapeutic agent directed specifically toward
tumors with high Akt activity could prove extremely potent in treating those
breast tumors with the most aggressive phenotypes. Several studies have demonstrated that
rapamycin, which inhibits
mammalian target of rapamycin (mTOR), a downstream target of Akt, sensitizes certain resistant
cancer cells to chemotherapeutic agents. This study evaluated the efficacy of mTOR inhibition in the treatment of
tamoxifen-resistant
breast carcinoma characterized by high Akt activity. We found that MCF-7
breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced
estrogen conditions and are resistant to the growth inhibitory effects of
tamoxifen, both in vitro as well as in vivo in xenograft models. Cotreatment with the mTOR inhibitor
rapamycin in vitro, or the
ester of
rapamycin,
CCI-779 (Wyeth) in vivo, inhibited mTOR activity and restored sensitivity to
tamoxifen, suggesting that Akt-induced
tamoxifen resistance is mediated in part by signaling through the mTOR pathway. Although the mechanism underlying the synergism remains to be understood, the results were associated with
rapamycin's ability to block transcriptional activity mediated by
estrogen receptor alpha, as assessed by reporter gene assays with
estrogen-responsive
element luciferase. These data corroborate prior findings indicating that Akt activation induces resistance to
tamoxifen in
breast cancer cells. Importantly, these data indicate a novel mechanism for
tamoxifen resistance and suggest that blockage of the
phosphatidylinositol 3'-kinase/Akt signaling pathway by mTOR inhibition effectively restores the susceptibility of these cells to
tamoxifen. These data may have implication for future clinical studies of mTOR inhibition in
breast carcinoma.