Targeting the Akt/mTOR pathway in Brca1-deficient cancers

Abstract

The breast cancer susceptibility gene 1 (Brca1) has a key role in both hereditary and sporadic mammary tumorigenesis. However, the reasons why Brca1-deficiency leads to the development of cancer are not clearly understood. Activation of Akt kinase is one of the most common molecular alterations associated with human malignancy. Increased Akt kinase activity has been reported in most breast cancers. We previously found that downregulation of Brca1 expression or mutations of the Brca1 gene activate the Akt oncogenic pathway. To further investigate the role of Brca1/Akt in tumorigenesis, we analyzed Brca1/Akt expression in human breast cancer samples and found that reduced expression of Brca1 was highly correlated with increased phosphorylation of Akt. Consistent with the clinical data, knockdown of Akt1 by short-hairpin RNA inhibited cellular proliferation of Brca1 mutant cells. Importantly, depletion of Akt1 significantly reduced tumor formation induced by Brca1-deficiency in mice. The third generation inhibitor of mammalian target of rapamycin (mTOR), Palomid 529, significantly suppressed Brca1-deficient tumor growth in mice through inhibition of both Akt and mTOR signaling. Our results indicate that activation of Akt is involved in Brca1-deficiency mediated tumorigenesis and that the mTOR pathway can be used as a novel target for treatment of Brca1-deficient cancers.

MRE11 promotes AKT phosphorylation in direct response to DNA double-strand breaks

“…68 This is consistent with our model of DNA damage-associated pAKT-S473, since BRCA1-associated tumors show high levels of genomic instability. Furthermore, Xiang and colleagues demonstrated that the increase in pAKT-S473 in BRCA1-deficient tumors was not associated with oncogenic mutations in PIK3CA, which further supports our model of PI3K-independent pAKT-S473 phosphorylation in response to DNA damage.…”

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

“…Further study by Kao et al [23] demonstrated that overexpression of PTEN resulted in decreased Akt1 phosphorylation and repair of DNA-DSB. This study does not support a role for increased Akt activity in hampering HR, as has been suggested by others [192][193][194]. However, if Akt activity leads to inhibiting HR, because DNA-DSB repair involves both the NHEJ and HR repair pathways, the negative effect of Akt on HR might be dominated by Akt-mediated stimulation of NHEJ.…”

“…HR deficiency is associated with increased phosphorylation of Akt1 at S743, as shown in breast cancer patients. Likewise, tumor formation due to BRCA1 deficiency is reduced by Akt1 depletion [192]. Inhibition of HR by Akt1 activity in BRCA1-proficient breast cancer cells has been demonstrated to be due to the induction of cytoplasmic retention of BRCA1 and RAD51 [193].…”

BRCA1 Induces Major Energetic Metabolism Reprogramming in Breast Cancer Cells

“…It has already been shown that AKT could be inactivated by BRCA1 [4], [36]. This major oncoprotein can induce glycolysis via multiple mechanisms, including expression and activation of hexokinases (AKT can phosphorylate HK2) and activation of PFK enzymes [29].…”