Herstatin inhibits heregulin-mediated breast cancer cell growth and overcomes tamoxifen resistance in breast cancer cells that overexpress HER-2.
Ligands of the ErbB family of receptors and estrogens control the proliferation of breast cancer cells. Overexpression of human EGF receptor HER-2 (erbB2) leads to amplified heregulin (HRG) signaling, promoting more aggressive breast cancer that is nonresponsive to estrogen and the antiestrogenic drug tamoxifen. Herstatin (Hst), a secreted HER-2 gene product, binds to the HER-2 receptor ectodomain blocking receptor activation. The aim of this study was to investigate the impact of this HER-2 inhibitor on HRG-induced signaling, proliferation, and sensitivity to tamoxifen in breast cancer cells with and without HER-2 overexpression. The expression of Hst in MCF7 cells eliminated HRG signaling through both mitogen-activated protein kinase and Akt pathways and prevented HRG-mediated proliferation. The loss in signaling corresponded to downregulation of the HRG receptors, HER-3 and HER-4, whereas HER-2 overexpression strongly stimulated the levels of both HRG receptors. Although Hst blocked HRG signaling in both parental and HER-2 transfected cells, it enhanced sensitivity to tamoxifen only in the MCF7 cells that overexpressed HER-2. To evaluate further the efficacy of Hst as an anticancer agent, His-tagged Hst was expressed in transfected insect cells, purified, and added to the breast cancer cells. As in the transfected cells, purified Hst inhibited HER-3 levels and suppressed HRG-induced proliferation of MCF7 and BT474 breast cancer cells. In contrast, the HER-2 monoclonal antibody, herceptin, downregulated HER-2, but not HER-3. These results suggest the potential use of Hst against HRG-mediated growth of breast cancers with high and low levels of HER-2 and against tamoxifen resistance in HER-2 overexpressing breast cancer.
Jhabvala-Romero
Farida
F
Department of Biochemistry and Molecular Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
Evans
Adam
A
Guo
Shuhua
S
Denton
Michael
M
Clinton
Gail Mary
GM
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020890:Neuregulin-1 / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D066247:Receptor, ErbB-4; D013629:Tamoxifen / Q000494:pharmacology*
D018931:Antineoplastic Agents, Hormonal; D002352:Carrier Proteins; D066246:ErbB Receptors; D036341:Intercellular Signaling Peptides and Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D013629:Tamoxifen; C434665:herstatin; C587689:ERBB4 protein, human