Estrogens decrease gamma-ray-induced senescence and maintain cell cycle progression in breast cancer cells independently of p53.
OBJECTIVE
Sequential administration of radiotherapy and endocrine therapy is considered to be a standard adjuvant treatment of breast cancer. Recent clinical reports suggest that radiotherapy could be more efficient in association with endocrine therapy. The aim of this study was to evaluate the estrogen effects on irradiated breast cancer cells (IR-cells).


METHODS
Using functional genomic analysis, we examined the effects of 17-beta-estradiol (E(2), a natural estrogen) on MCF-7 breast cancer cells.


RESULTS
Our results showed that E(2) sustained the growth of IR-cells. Specifically, estrogens prevented cell cycle blockade induced by gamma-rays, and no modification of apoptotic rate was detected. In IR-cells we observed the induction of genes involved in premature senescence and cell cycle progression and investigated the effects of E(2) on the p53/p21(waf1/cip1)/Rb pathways. We found that E(2) did not affect p53 activation but it decreased cyclin E binding to p21(waf1/cip1) and sustained downstream Rb hyperphosphorylation by functional inactivation of p21(waf1/cip1). We suggest that Rb inactivation could decrease senescence and allow cell cycle progression in IR-cells.


CONCLUSIONS
These results may help to elucidate the molecular mechanism underlying the maintenance of breast cancer cell growth by E(2) after irradiation-induced damage. They also offer clinicians a rational basis for the sequential administration of ionizing radiation and endocrine therapies.
Toillon
Robert-Alain
RA
Laboratoire Jean-Claude Heuson de Cancérologie Mammaire, Université Libre de Bruxelles, Brussels, Belgium. robert.toillon@univlillel.fr
Magné
Nicolas
N
Laïos
Ioanna
I
Castadot
Pierre
P
Kinnaert
Eric
E
Van Houtte
Paul
P
Desmedt
Christine
C
Leclercq
Guy
G
Lacroix
Marc
M
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D019927:Cyclin E / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D005720:Gamma Rays / Q000627:therapeutic use*; D006801:Humans; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism
C493956:CDKN1A protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D004958:Estradiol