Estrogen withdrawal-induced NF-kappaB activity and bcl-3 expression in breast cancer cells: roles in growth and hormone independence.
About one-third of breast cancers express a functional estrogen (beta-estradiol [E2]) receptor (ER) and are initially dependent on E2 for growth and survival but eventually progress to hormone independence. We show here that ER(+), E2-independent MCF-7/LCC1 cells derived from E2-dependent MCF-7 cells contain elevated basal NF-kappaB activity and elevated expression of the transcriptional coactivator Bcl-3 compared with the parental MCF-7 line. LCC1 NF-kappaB activity consists primarily of p50 dimers, although low levels of a p65/p50 complex are also present. The ER(-) breast cancer cell lines harbor abundant levels of both NF-kappaB complexes. In contrast, nuclear extracts from MCF-7 cells contain a significantly lower level of p50 and p65 than do LCC1 cells. Estrogen withdrawal increases both NF-kappaB DNA binding activity and expression of Bcl-3 in MCF-7 and LCC1 cells in vitro and in vivo. Tumors derived from MCF-7 cells ectopically expressing Bcl-3 remain E2 dependent but display a markedly higher tumor establishment and growth rate compared to controls. Expression of a stable form of IkappaBalpha in LCC1 cells severely reduced nuclear expression of p65 and the p65/p50 DNA binding heterodimer. Whereas LCC1 tumors in nude mice were stable or grew, LCC1(IkappaBalpha) tumors regressed after E2 withdrawal. Thus, both p50/Bcl-3- and p65/p50-associated NF-kappaB activities are activated early in progression and serve differential roles in growth and hormone independence, respectively. We propose that E2 withdrawal may initiate selection for hormone independence in breast cancer cells by activation of NF-kappaB and Bcl-3, which could then supplant E2 by providing both survival and growth signals.
Pratt
M A Christine
MA
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5. cpratt@uottawa.ca
Bishop
Tanya E
TE
White
Dawn
D
Yasvinski
Gordon
G
Ménard
Michel
M
Niu
Min Ying
MY
Clarke
Robert
R
D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics; D009368:Neoplasm Transplantation; D009857:Oncogenes; D010052:Ovariectomy; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse; D004268:DNA-Binding Proteins; D004967:Estrogens; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors