Journal
MOLECULAR CANCER RESEARCH
Volume 11, Issue 10, Pages 1269-1278Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-13-0212
Keywords
-
Categories
Funding
- National Natural Science Fundation of China [81202087, 81172520, 81202088, 81071747, 81272404]
- National key program (973) for Basic Research of China [2011CB510106, 2011CB504300]
- Leading Academic Discipline Project of Shanghai Municipal Education Commission [J50208]
- Shanghai Science and Technology Committee [12ZR1446400]
- Program for Professor of Special Appointment at Shanghai Institutions of Higher Learning
- Shanghai Pujiang Program [10PJ1406400]
- Program of Shanghai Municipal Health Bureau Subject Chief Scientist [XBR20110052]
Ask authors/readers for more resources
Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor-positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells (MCF-7 and BT474), everolimus inhibited the mTOR downstream activity by limiting phosphorylation of p70S6K and 4EBP1, which resulted in p-Ser473-AKT activation. However, addition of a LY294002, a PI3K inhibitor, to tamoxifen and everolimus treatment improved the antitumor effect compared with tamoxifen alone or the other two agents in combination. Moreover, LY294002 suppressed the activity of the PI3K/AKT/mTOR axis and mitigated the p-Ser473-AKT activation feedback loop in both cell lines. Critically, this combination scheme also significantly inhibited the expression of HIF-1a, an angiogenesis marker, under hypoxic conditions and reduced blood vessel sprout formation in vitro. Finally, it was shown that the three-agent cocktail had the greatest efficacy in inhibiting MCF-7 xenograft tumor growth and angiogenesis. Taken together, these results suggest that inhibition of PI3K and mTOR may further improve therapy in ER+ breast cancer cells. Implications: Combinatorial inhibition of the PI3K/AKT/mTOR signaling axis may enhance endocrine-based therapy in breast cancer.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available