Tumor metastasis is the major cause of cancer-related death in most types of human cancers including breast cancer. The long-term goal of our research is to better understand molecular mechanisms of alternative splicing underlying breast cancer metastasis. In this project we propose to investigate the mechanisms of a positive feedback loop involving the CD44s splice isoform and Akt activation that is responsible for breast tumor metastasis. The cell surface molecule CD44 is comprised of a family of proteins that are generated by alternative splicing. Inclusion of different combinations of variable exons generates CD44v. Conversely, exclusion of all of the variable exons produces CD44s. CD44 can be viewed as a sensor for extracellular cues. By forming co-receptor complexes with receptor tyrosine kinases (RTKs) and their growth factors, CD44 augments growth factor-stimulated RTK signaling. Our previous studies showed that CD44v and CD44s act on different signaling cascades: CD44s activates Akt signaling that is critical for promoting cell survival, while CD44v, on the other hand, promotes Ras/MAPK signaling resulting in a cell proliferative state. We recently reported that the CD44s isoform plays an essential role in epithelial-mesenchymal transition (EMT), a developmental process that is abnormally activated in tumor metastasis. We also found that depletion of CD44 by shRNA inhibits breast tumor metastasis in animals and that CD44s expression is upregulated in high-grade patient breast tumor specimens. These results suggest a critical role for CD44s in breast cancer metastasis. Mechanistically, we have shown that CD44s potentiates Akt activation and promotes cell survival. We also found that CD44s-dependent Akt signaling upregulates hyaluronic acid synthase 2 (HAS2) expression. Importantly, the HAS2 product, hyaluronic acid (HA), is a ligand that binds to CD44 and facilitates CD44s- mediated Akt activation. These observations led us to hypothesize that a positive feedback loop couples CD44s and Akt signaling, resulting in sustained Akt activation and promoting breast cancer metastasis. To test our hypothesis we have developed the following specific aims:
Aim 1, Determine the molecular mechanism by which CD44s activates Akt signaling.
Aim 2, Examine how CD44s-dependent Akt activation promotes HAS2 expression in breast cancer cells.
Aim 3, Investigate whether HA, product of HAS2, promotes CD44s-dependent Akt activation and examine the positive-feedback loop in clinical breast tumor metastasis. Successfully accomplishing this project will define a novel mechanism of a positive feedback loop that promotes breast tumor metastasis. Intervening this positive feedback loop could offer an exciting new therapeutic approach for the treatment of metastatic breast cancer.
Breast cancer metastasis remains as a major obstacle for the treatment of breast cancer. The primary goal of this proposal is to investigate the mechanisms by which CD44 promotes breast cancer metastasis. A better understanding and identification of new regulatory mechanisms in cancer pathogenesis will facilitate the development of new strategies for the treatment of metastatic breast cancer.
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