Differential expression of VEGF-A mRNA by 17beta-estradiol in breast tumor cells lacking classical ER-alpha may be mediated through a variant form of ER-alpha.
Beta-estradiol (17beta-E2) augments VEGF-A expression in various estrogen targeted organs and cells including breast tumor derived cell lines, via an ER-alpha mediated pathway. Ironically, 17beta-E2 is able to regulate some genes via ER-alpha independent pathways. In the present study, we sought to determine whether 17beta-E2 can modulate VEGF-A expression in absence of ER-alpha, and therefore, three different cell lines including ER-alpha+ MCF-7, and ER-alpha SKBR-3 and HMEC were used for this study. The present study demonstrates that 17beta-E2 also induces VEGF-A mRNA expression in ER-negative SKBR-3 breast tumor cells in a manner similar to that observed in ER-positive MCF-7 cells. Blocking the induced-expression by antiestrogen ICI 182,780 indicates the induction pathway is ER dependent. While ER-alpha mRNA is absent in both HMEC and SKBR-3 cells, the impact of estrogen was found only in SKBR-3 cells, suggesting the existence of an analogue to ER-alpha or overlapping signal in these cells. Consistent with this suggestion, the present studies demonstrate the existence of an ER-alpha(var2) protein in MCF-7 and in SKBR-3 cells. This variant is predominantly localized in the nuclei of SKBR-3 cells. Importantly, specific binding of 17beta-E2 by these cells suggest the ER-alpha(var2) may act as active receptor in SKBR-3 cells.
Sengupta
Krishanu
K
Cancer Research Unit, V.A. Medical Center, Kansas City, MO 64128-2226, USA.
Banerjee
Snigdha
S
Saxena
Neela K
NK
Jonathan
Nira Ben
NB
Campbell
Donald R
DR
Banerjee
Sushanta K
SK
D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D014644:Genetic Variation; D006801:Humans; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D011869:Radioligand Assay; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol