Role of estrogen receptor in the regulation of ecto-5'-nucleotidase and adenosine in breast cancer.
OBJECTIVE
The purpose is to understand the expression of ecto-5'-nucleotidase (eN), an adenosine producing enzyme with potential roles in angiogenesis, growth, and immunosuppression, in estrogen receptor (ER)-negative and -positive breast cancer.


METHODS
We investigated the regulation of eN expression at the mRNA and protein levels by alpha in a panel of breast cancer cell lines that differ in ER status and invasive and metastatic potential. We also determined rates of adenosine formation in cells with high and low eN expression and in ER+ cells treated with estradiol.


RESULTS
ER-negative cells express high eN protein and mRNA levels and produce up to 104-fold more adenosine from AMP and ATP. Estradiol and antiestrogen treatments confirm that eN mRNA and protein expression and adenosine generation are negatively regulated through the ER. Endogenous expression of eN in ER- cells transfected with ERalpha and phorbol ester-induced eN expression in ER+ cells was strongly suppressed by estradiol, suggesting a dominant function of ER. Finally, an examination of 18 clinical breast cancer samples that were analyzed for both ER status and eN expression by Martin et al. (Cancer Res., 60: 2232-2238, 2000) revealed a significant inverse correlation between ER and eN status.


CONCLUSIONS
Our results show for the first time that eN is negatively regulated by ERalpha in dominant fashion and suggests that eN expression and its generation of adenosine may relate to breast cancer progression. Additionally, increased expression of eN in a subset of ER-negative cells may serve as a novel marker for a subset of more aggressive breast carcinoma.
Spychala
Jozef
J
Department of Pharmacology, Lineberger Comprehensive Cancer Center, Cystic Fibrosis Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA. jozek@med.unc.edu
Lazarowski
Eduardo
E
Ostapkowicz
Anna
A
Ayscue
Lanier H
LH
Jin
Aiwen
A
Mitchell
Beverly S
BS
D015720:5'-Nucleotidase / Q000378:metabolism*; D000241:Adenosine / Q000737:chemistry / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D018450:Disease Progression; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010703:Phorbol Esters / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D004967:Estrogens; D010703:Phorbol Esters; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D000249:Adenosine Monophosphate; D004958:Estradiol; D000255:Adenosine Triphosphate; D015720:5'-Nucleotidase; D000243:Adenosine Deaminase; D000241:Adenosine