Activation of PI3K/Akt signaling and hormone resistance in breast cancer.

Akt is a serine/threonine kinase that has been demonstrated to play an important role in survival when cells are exposed to different apoptotic stimuli. Recent studies show that aberrant activation of Akt in breast carcinoma is associated with a poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway is currently attracting considerable attention as a new target for effective therapeutic strategies. We investigated the incidence of Akt activation in 252 primary breast carcinomas and relationships among the activation of Akt, HER2 overexpression, hormone receptor expression, and alteration of the PTEN gene. Eighty-four cases (33.3%) were positive for pAkt expression. pAkt was significantly associated with HER2 overexpression (p<0.0001) and LOH at the PTEN gene locus (p<0.01). There was an inverse correlation between pAkt and PR (p<0.05). We also retrospectively examined the relationship between Akt activation and the efficacy of endocrine therapy for metastatic breast cancer. Of these 36 metastatic breast cancer cases, 12 cases (33.4%) were considered to show positive pAkt expression. In the pAkt-positive patients, endocrine therapy demonstrated worse efficacy than in pAkt-negative patients (p<0.01). In addition, the clinical benefit was the smallest in the patients positive both for HER2 and pAkt (p<0.01). The clinical benefit rate of estrogen deprivation therapy with AI or LH-RH agonist was significantly lower in the pAkt-positive patients than that in the pAkt-negative ones (p<0.05), and there was a tendency for the clinical benefit of SERM to be smaller in the pAkt-positive patients (p=0.09). These findings therefore suggest that Akt activation induces endocrine resistance in metastatic breast cancer, irrespective of the kind of endocrine agents that were administered. Our findings indicate that the activation of Akt in the downstream pathway of HER2 plays an important role in resistance to endocrine therapy for breast cancer. Our findings suggest that pAkt may be a useful predictor of resistance to endocrine therapy for breast cancer, while also suggesting that the inhibition of Akt may increase the efficacy of endocrine therapy.