A deletion mutant of heregulin increases the sensitivity of breast cancer cells to chemotherapy without promoting tumorigenicity.
Heregulin (HRG) is an activator of the erbB2-, erbB3- and erbB4-(erbB-2/3/4) signaling pathway. Transfection of full-length HRG cDNA into the estrogen (E2)-dependent cell line MCF-7 promoted an invasive E2-independent phenotype, as well as persistent activation of the erbB-2/3/4 receptors. Moreover, HRG expression in MCF-7 cells renders the cells sensitive to the topoisomerase II inhibitor doxorubicin (Doxo). In an attempt to dissociate the tumorigenic effect of HRG from the sensitizing effect to chemotherapy, we constructed a structural deletion mutant of HRG. Transfection of the deletion mutant of HRG described in this study (HRG/M) into MCF-7 cells resulted in the dissociation of the tumor-promoting activity of HRG from the sensitization to Doxo, that is, although the cells did not become more aggressive or E2-independent they became more sensitive to Doxo. HRG/M was unable to autophosphorylate the erbB receptors and did not affect the level of MAPK phosphorylation. Furthermore, the intracellular localization of the protein was different from that of the full-length protein. Our data show that the HRG/M sequences are sufficient to sensitize MCF-7 cells to Doxo, and provide evidence that this sensitization is independent of erbB2 activation.
Atlas
Ella
E
Evanston Northwestern Healthcare Research Institute, Northwestern University, 1001 University Place, 2650 Ridge Avenue Evanston, IL 60201, USA.
Bojanowski
Kozystof
K
Mehmi
Inderjit
I
Lupu
Ruth
R
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D003470:Culture Media / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D014162:Transfection; D014407:Tumor Cells, Cultured
D003470:Culture Media; D020890:Neuregulin-1; D004317:Doxorubicin