Akt Signaling Is Sustained by a CD44 Splice Isoform-Mediated Positive Feedback Loop

Cancer Res. 2017 Jul 15;77(14):3791-3801. doi: 10.1158/0008-5472.CAN-16-2545. Epub 2017 May 22.


Tumor cells nearly invariably evolve sustained PI3K/Akt signaling as an effective means to circumvent apoptosis and maintain survival. However, for those tumor cells that do not acquire PI3K/Akt mutations to achieve this end, the underlying mechanisms have remained obscure. Here, we describe the discovery of a splice isoform-dependent positive feedback loop that is essential to sustain PI3K/Akt signaling in breast cancer. Splice isoform CD44s promoted expression of the hyaluronan synthase HAS2 by activating the Akt signaling cascade. The HAS2 product hyaluronan further stimulated CD44s-mediated Akt signaling, creating a feed-forward signaling circuit that promoted tumor cell survival. Mechanistically, we identified FOXO1 as a bona fide transcriptional repressor of HAS2. Akt-mediated phosphorylation of FOXO1 relieved its suppression of HAS2 transcription, with FOXO1 phosphorylation status maintained by operation of the positive feedback loop. In clinical specimens of breast cancer, we established that the expression of CD44s and HAS2 was positively correlated. Our results establish a positive feedback mechanism that sustains PI3K/Akt signaling in tumor cells, further illuminating the nearly universal role of this pathway in cancer cell survival. Cancer Res; 77(14); 3791-801. ©2017 AACR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Survival / physiology
  • Feedback, Physiological
  • Female
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • HEK293 Cells
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Hyaluronan Synthases
  • Protein Isoforms
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction


  • CD44 protein, human
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Hyaluronan Receptors
  • Protein Isoforms
  • Glucuronosyltransferase
  • HAS2 protein, human
  • Hyaluronan Synthases
  • Proto-Oncogene Proteins c-akt