Compositions and methods for modulating left-right differentiation factor (LEFTY) and bone morphogenic factor (BMP)
This disclosure provides data showing that LEFTY inhibits differentiation-promoting pathways such as BMP7/pSMAD5 in breast cancer cell lines, over and above its known role of inhibiting Nodal/pSMAD2. LEFTY competes with BMP7 to bind to its cell surface receptor BMPR2, leading to inhibition of pSMAD5. The LEFTY-BMPR2 interaction is dominant over BMP-BMPR2 in tumorigenic cells, resulting in diminished pSMAD status, whereas in non-tumorigenic cells, there is minimal LEFTY-BMPR2 interaction, increased BMP7-BMPR2 association, and elevated pSMAD. Compositions and methods for inducing or inhibiting expression and/or the activity of LEFTY and BMP proteins are described, which can be used in diagnosis and therapy of cancer and other conditions, and to promote proliferation of stem cells.
1. A method of treating a patient having a cancer, the method comprising administering to the patient a therapeutic amount of an agent that antagonizes the expression or activity of a left-right determination factor (LEFTY), wherein the cancer is breast cancer, and wherein the agent is:
(a) an inhibitory RNA, or a plasmid or a vector encoding the inhibitory RNA, wherein the inhibitory RNA binds to a target sequence in a LEFTY polynucleotide;
(b) an anti-LEFTY antibody or an antigen-binding fragment thereof; or
(c) a blocking peptide against a LEFTY protein.
2. The method of claim 1 , wherein a genomic amplification of a gene that encodes the LEFTY protein or expression of a LEFTY mRNA or the LEFTY protein has been detected in a biological sample from the patient.
3. The method of claim 1 , wherein the breast cancer comprises cells that express LEFTY1 mRNA or LEFTY1 protein.
4. The method of claim 1 , wherein the agent is the inhibitory RNA or the plasmid or the vector encoding the inhibitory RNA.
5. The method of claim 4 , wherein the agent is the inhibitory RNA.
6. The method of claim 4 , wherein the inhibitory RNA is a short hairpin RNA (shRNA).
7. The method of claim 1 , wherein the agent inhibits interaction between a LEFTY protein and BMPR2.
8. The method of claim 1 , wherein the agent is a blocking or neutralizing antibody against the LEFTY protein or an antigen-binding fragment of the antibody.
9. The method of claim 1 , wherein said LEFTY is LEFTY1.
10. The method of claim 1 , wherein the agent is the anti-LEFTY antibody or the antigen-binding fragment thereof.
11. The method of claim 10 , wherein the agent is the anti-LEFTY antibody.
12. The method of claim 8 , wherein the agent is the blocking antibody against the LEFTY protein or the antigen-binding fragment thereof.
13. The method of claim 12 , wherein the agent is the blocking antibody against the LEFTY protein.
14. The method of claim 1 , wherein the agent is the blocking peptide against the LEFTY protein.
15. The method of claim 1 , wherein the treating comprises inhibiting one or more of breast cancer tumor growth, breast cancer tumor formation, or proliferation of breast cancer cells in the patient.
16. The method of claim 1 , wherein the treating comprise inhibiting tumorigenic characteristics of cells of the breast cancer in the patient.