TY - JOUR
T1 - Immunotherapeutic potential of anti-human endogenous retrovirus-k envelope protein antibodies in targeting breast tumors
AU - Wang-Johanning, Feng
AU - Rycaj, Kiera
AU - Plummer, Joshua B.
AU - Li, Ming
AU - Yin, Bingnan
AU - Frerich, Katherine
AU - Garza, Jeremy G.
AU - Shen, Jianjun
AU - Lin, Kevin
AU - Yan, Peisha
AU - Glynn, Sharon A.
AU - Dorsey, Tiffany H.
AU - Hunt, Kelly K.
AU - Ambs, Stefan
AU - Johanning, Gary L.
N1 - Funding Information:
This work was supported in part by the Department of Defense (BC052782 to F.W.-J), Susan G. Komen for the Cure (BCTR0402892 to F.W.-J), the National Institute of Environmental Health Sciences (ES007784 to G.L.J.), the Avon Foundation (07-2007-070 01 to G.L.J.), seed money provided by the Cattleman for Cancer Research Foundation (to F.W.-J and G.L.J.), and MD Anderson Cancer Center startup funds (to F.W.-J).
PY - 2012/2/8
Y1 - 2012/2/8
N2 - Background The envelope (env) protein of the human endogenous retrovirus type K (HERV-K) family is commonly expressed on the surface of breast cancer cells. We assessed whether HERV-K env is a potential target for antibody-based immunotherapy of breast cancer. Methods We examined the expression of HERV-K env protein in various malignant (MDA-MB-231, MCF-7, SKBR3, MDA-MB-453, T47D, and ZR-75-1) and nonmalignant (MCF-10A and MCF-10AT) human breast cell lines by immunoblot, enzyme-linked immunosorbent assay, immunofluorescence staining, and flow cytometry. Anti-HERV-K env monoclonal antibodies (mAbs; 6H5, 4D1, 4E11, 6E11, and 4E6) were used to target expression of HERV-K, and antitumor effects were assessed by quantifying growth and apoptosis of breast cancer cells in vitro, and tumor growth in vivo in mice (n = 5 per group) bearing xenograft tumors. The mechanisms responsible for 6H5 mAb-mediated effects were investigated by microarray assays, flow cytometry, immunoblot, and immunofluorescence staining. The expression of HERV-K env protein was assessed in primary breast tumors (n = 223) by immunohistochemistry. All statistical tests were two-sided. Results The expression of HERV-K env protein in malignant breast cancer cell lines was substantially higher than nonmalignant breast cells. Anti-HERV-K-specific mAbs inhibited growth and induced apoptosis of breast cancer cells in vitro. Mice treated with 6H5 mAb showed statistically significantly reduced growth of xenograft tumors compared with mice treated with control immunoglobulin (control [mIgG] vs 6H5 mAb, for tumors originating from MDA-MB-231 cells, mean size = 1448.33 vs 475.44 mm 3; difference = 972.89 mm 3, 95% CI = 470.17 to 1475.61 mm 3; P < .001). Several proteins involved in the apoptotic signaling pathways were overexpressed in vitro in 6H5 mAb-treated malignant breast cells compared with mIgG-treated control. HERV-K expression was detected in 148 (66%) of 223 primary breast tumors, and a higher rate of lymph node metastasis was associated with HERV-K-positive compared with HERV-K-negative tumors (43% vs 23%, P =. 003). Conclusion Monoclonal antibodies against HERV-K env protein show potential as novel immunotherapeutic agents for breast cancer therapy.
AB - Background The envelope (env) protein of the human endogenous retrovirus type K (HERV-K) family is commonly expressed on the surface of breast cancer cells. We assessed whether HERV-K env is a potential target for antibody-based immunotherapy of breast cancer. Methods We examined the expression of HERV-K env protein in various malignant (MDA-MB-231, MCF-7, SKBR3, MDA-MB-453, T47D, and ZR-75-1) and nonmalignant (MCF-10A and MCF-10AT) human breast cell lines by immunoblot, enzyme-linked immunosorbent assay, immunofluorescence staining, and flow cytometry. Anti-HERV-K env monoclonal antibodies (mAbs; 6H5, 4D1, 4E11, 6E11, and 4E6) were used to target expression of HERV-K, and antitumor effects were assessed by quantifying growth and apoptosis of breast cancer cells in vitro, and tumor growth in vivo in mice (n = 5 per group) bearing xenograft tumors. The mechanisms responsible for 6H5 mAb-mediated effects were investigated by microarray assays, flow cytometry, immunoblot, and immunofluorescence staining. The expression of HERV-K env protein was assessed in primary breast tumors (n = 223) by immunohistochemistry. All statistical tests were two-sided. Results The expression of HERV-K env protein in malignant breast cancer cell lines was substantially higher than nonmalignant breast cells. Anti-HERV-K-specific mAbs inhibited growth and induced apoptosis of breast cancer cells in vitro. Mice treated with 6H5 mAb showed statistically significantly reduced growth of xenograft tumors compared with mice treated with control immunoglobulin (control [mIgG] vs 6H5 mAb, for tumors originating from MDA-MB-231 cells, mean size = 1448.33 vs 475.44 mm 3; difference = 972.89 mm 3, 95% CI = 470.17 to 1475.61 mm 3; P < .001). Several proteins involved in the apoptotic signaling pathways were overexpressed in vitro in 6H5 mAb-treated malignant breast cells compared with mIgG-treated control. HERV-K expression was detected in 148 (66%) of 223 primary breast tumors, and a higher rate of lymph node metastasis was associated with HERV-K-positive compared with HERV-K-negative tumors (43% vs 23%, P =. 003). Conclusion Monoclonal antibodies against HERV-K env protein show potential as novel immunotherapeutic agents for breast cancer therapy.
UR - https://www.scopus.com/pages/publications/84863177511
UR - https://www.scopus.com/pages/publications/84863177511#tab=citedBy
U2 - 10.1093/jnci/djr540
DO - 10.1093/jnci/djr540
M3 - Article
C2 - 22247020
AN - SCOPUS:84863177511
SN - 0027-8874
VL - 104
SP - 189
EP - 210
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 3
ER -