17beta-Oestradiol treatment modulates nitric oxide synthase activity in MDA231 tumour with implications on growth and radiation response.
The putative oestrogen receptor negative human breast cancer cell line MDA231, when grown as tumours in mice continually receiving 17beta-oestradiol, showed substantially increased growth rate when compared to control animals. Further, we observed that 17beta-oestradiol treatment could both increase the growth rate of established MDA231 tumours as well as decreasing the time taken for initiating tumour growth. We have also demonstrated that this increase in growth rate is accompanied by a four-fold increase in nitric oxide synthase activity, which was predominantly the inducible form. Inducible-nitric oxide synthase expression in these tumours was confirmed by immunohistochemical analysis and appeared localized primarily in areas between viable and necrotic regions of the tumour (an area that is presumably hypoxic). Prophylactic treatment with the nitric oxide synthase inhibitor nitro-L-arginine methyl ester resulted in significant reduction in this apparent 17beta-oestradiol-mediated growth promoting effect. Tumours derived from mice receiving 17beta-oestradiol-treatment were characterized by a significantly lower fraction of perfused blood vessels and an indication of an increased hypoxic fraction. Consistent with these observations, 17beta-oestradiol-treated tumours were less radio-responsive compared to control tumours when treated with a single radiation dose of 15 Gy. Our data suggests that long-term treatment with oestrogen could significantly alter the tumour oxygenation status during breast tumour progression, thus affecting response to radiotherapy.
Chinje
E C
EC
Experimental Oncology Group, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK. edwin.chinje@man.ac.uk
Williams
K J
KJ
Telfer
B A
BA
Wood
P J
PJ
van der Kogel
A J
AJ
Stratford
I J
IJ
D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000532:radiotherapy*; D015687:Cell Hypoxia; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000032:analysis; D014407:Tumor Cells, Cultured
D011960:Receptors, Estrogen; D004958:Estradiol; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester