title: Involvement of heregulin-beta2 in the acquisition of the hormone-independent phenotype of breast cancer cells.
abstract: The erbB-2 receptor plays an important role in the prognosis of breast cancer. Amplification or overexpression of the erbB-2 proto-oncogene has been detected in 30% of breast cancers and is associated with poor patient prognosis. The significance of erbB-3 and erbB-4 in breast cancer is not yet known. The discovery of the growth factor heregulin (HRG) has allowed us to investigate a number of biological events that are regulated by erbB-2, -3, and -4 signal transduction. To determine the role of HRG in breast cancer tumor progression, we have developed an in vitro/in vivo model. We transfected HRG cDNA into the estrogen receptor (ER)-positive breast cancer cell line, MCF-7, and studied these cells as they progressed from a hormone-dependent to -independent phenotype. The biochemical and biological characteristics presented here demonstrate that overexpression of HRG induces morphological changes in MCF-7 cells as well as erbB-2, erbB-3, and erbB-4 autophosphorylation. MCF-7/ heregulin-transfected cells, which express relatively high levels of HRG, developed estrogen independence and resistance to antiestrogens in vitro and in vivo. This is consistent with a more aggressive hormone-independent phenotype. In contrast with control parental/wild-type cells, estradiol-mediated down-regulation of erbB-2 expression is blocked completely in this particular model system. These results indicate that HRG plays a role in the disruption of ER function. When a transient transfection with an ERE-CAT construct was introduced into these HRG-transfected MCF-7 cells, we observed that the ER was transcriptionally inactive. This suggests that ER signaling is altered in HRG-transfected cells. We observed that overexpression of HRG induces a more aggressive, hormone-independent phenotype that is most likely directly related to the constitutive activation of the erbB-2, erbB-3, and erbB-4 receptor signaling cascade. The data presented here suggest a close cross-regulation between the erbB-2/4 receptors and ER and provide new insights into the mechanism by which breast cancer cells acquire a hormone-independent phenotype.
authors.affiliation: Vincent T. Lombardi Cancer Center, Georgetown University, Washington, D.C. 20007, USA.
authors.forename: C K
authors.initials: CK
authors.lastname: Tang
authors.forename: C
authors.initials: C
authors.lastname: Perez
authors.forename: T
authors.initials: T
authors.lastname: Grunt
authors.forename: C
authors.initials: C
authors.lastname: Waibel
authors.forename: C
authors.initials: C
authors.lastname: Cho
authors.forename: R
authors.initials: R
authors.lastname: Lupu
mesh_terms: D001943:Breast Neoplasms / Q000503:physiopathology*; D002352:Carrier Proteins / Q000502:physiology*; D002455:Cell Division; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000502:physiology*; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D020890:Neuregulin-1; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology; D011980:Receptors, Progesterone / Q000502:physiology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D018076:DNA, Complementary; D006023:Glycoproteins; D006133:Growth Substances; D020890:Neuregulin-1; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C000715470:MAS1 protein, human; C087230:heregulin beta1