Abstract
Anthracyclines are key components of human breast cancer chemotherapy. Here, we explored the role of Akt signaling in anthracycline resistance.The antitumor activity of doxorubicin and Akt inhibitor A-443654 alone or combined was examined in estrogen receptor (ER) positive and negative human breast cancer cell lines. Further, we examined mRNA changes induced by anthracyclines in locally advanced breast cancers biopsied before and after treatment in two clinical trials.Doxorubicin increased Akt phosphorylation in ER positive MCF7 and T47D cell lines, with no effect in ER negative MDA-MB231 breast cancer cells. A-443654 was significantly more cytotoxic in doxorubicin-resistant compared to doxorubicin-naïve MCF7. This difference was not observed in MDA-MB231. Among 24 patients, AKT1 gene expression increased 24 hrs after the initial epirubicin exposure in ER positive tumors responding to therapy (n=6), as compared to ER positive non-responders (n=7) or ER negative tumors (n=11). In contrast, AKT1 mRNA changes after 16 weeks of doxorubicin were unrelated to clinical response and ER status (n=30).In conclusion, rapid Akt activation was observed in ER positive breast cancers which responded to anthracyclines. Increased cytotoxicity of A-443654 in doxorubicin-resistant MCF7 cells indicates a possible role for Akt inhibitors in ER positive breast cancers where chemoresistance evolves.
Highlights
Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-Akt-mammalian target of rapamycin-S6 kinase (S6K) signaling is upregulated in 25% of human breast cancers and has been associated with resistance to endocrine as well as HER2 directed therapy [1,2,3]
Inhibitors of the PI3K-Akt-mammalian target of rapamycin (mTOR) pathway can be employed to www.impactjournals.com/oncotarget enhance anthracycline sensitivity in estrogen receptor (ER) positive breast cancers [10, 11] Whereas the introduction of Akt inhibitors in clinical trials has been slower than PI3K and mTOR inhibitors [12], the key position of Akt as a signal hub for important pro-tumorigenic pathways [6] makes such trials highly relevant
Whereas doxorubicin had no impact on Phosphatase and tensin homolog (PTEN) protein levels in neither cell line, mTOR phosphorylation levels increased in MB231 and decreased in MCF7 cells (Figure 1A1B), not significant by densitometry (Figure 1E-1F)
Summary
Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR)-S6 kinase (S6K) signaling (in short: PI3K signaling) is upregulated in 25% of human breast cancers and has been associated with resistance to endocrine as well as HER2 directed therapy [1,2,3]. PIK3CA, encoding the p110α subunit of PI3K, harbors activating mutations in up to 45% of luminal A breast cancers [4], which are typically estrogen receptor (ER) positive tumors. Therapeutic inhibition of the PI3K signaling pathway with the mTOR inhibitor everolimus can be used to counteract acquired resistance to aromatase inhibitors and prolong survival among patients with ER positive breast cancer [3]. While experimental studies revealed loss of PTEN function to be associated with reduced sensitivity to doxorubicin in breast and prostate cancer models, chemosensitivity was restored by concomitant mTOR inhibition [7, 8]. Increased Akt phosphorylation is observed in doxorubicin-resistant ER positive, but not in ER negative breast cancer cell lines [9,10,11]. Inhibitors of the PI3K-Akt-mTOR pathway can be employed to www.impactjournals.com/oncotarget enhance anthracycline sensitivity in ER positive breast cancers [10, 11] Whereas the introduction of Akt inhibitors in clinical trials has been slower than PI3K and mTOR inhibitors [12], the key position of Akt as a signal hub for important pro-tumorigenic pathways [6] makes such trials highly relevant
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