17β-estradiol enhances α(5) integrin subunit gene expression through ERα-Sp1 interaction and reduces cell motility and invasion of ERα-positive breast cancer cells.
In breast tumors the expression of estrogen receptor alpha (ERα) is known to be associated with a more favorable prognosis. ERα expression has been reported to reduce the metastatic potential of breast cancer cells. Recently, we have observed that extracellular matrix proteins activate ERα and that both liganded and unliganded receptor modulate cell invasiveness acting at nuclear level. To explain the mechanisms by which ERα regulates cell adhesion, we have evaluated the expression of α(5)β(1) integrin, prevalently expressed in stationary cells, in response to 17β-estradiol (E2). Here we show that E2/ERα increases the expression of integrin α(5)β(1) through Sp1-mediated binding to a GC-rich region located upstream of an ERE half-site in the 5' flanking region of the α(5) gene forming a ternary ERα-Sp1-DNA complex. Estrogen responsiveness of the α(5) gene promoter, as observed in HeLa cells, underlies a general mechanism of regulation which is not strictly linked to the cell type. Our data reveal novel insight into the molecular mechanisms sustaining the reduced invasiveness of ERα expressing cells demonstrating that α(5)β(1) integrin expression is related to the maintenance of the stationary status of the cells, counteracting E2/ERα capability to enhance breast cancer cell migration and invasion.
Sisci
Diego
D
Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Italy.
Middea
Emilia
E
Morelli
Catia
C
Lanzino
Marilena
M
Aquila
Saveria
S
Rizza
Pietro
P
Catalano
Stefania
S
Casaburi
Ivan
I
Maggiolini
Marcello
M
Andò
Sebastiano
S
D024506:5' Flanking Region; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D039482:Integrin alpha5 / Q000235:genetics / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
D047628:Estrogen Receptor alpha; D039482:Integrin alpha5; D039081:Integrin alpha5beta1; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor