Hormone escape is associated with genomic instability in a human prostate cancer model.
Lack of hormone dependency in prostate cancers is an irreversible event that occurs through generation of genomic instability induced by androgen deprivation. Indeed, the cytogenetic profile of hormone-dependent (HD) prostate cancer remains stable as long as it received a hormone supply, whereas the profile of hormone-independent (HID) variants acquired new and various alterations. This is demonstrated here using a HD xenografted model of a human prostate cancer, PAC120, transplanted for 11 years into male nude mice and 4 HID variants obtained by surgical castration. Cytogenetic analysis, done by karyotype, FISH, CGH and array-CGH, shows that PAC120 at early passage presents numerous chromosomal alterations. Very few additional alterations were found between the 5th and 47th passages, indicating the stability of the parental tumor. HID variants largely maintained the core of chromosomal alterations of PAC120 - losses at 6q, 7p, 12q, 15q and 17q sites. However, each HID variant displayed a number of new alterations, almost all being specific to each variant and very few shared by all. None of the HID had androgen receptor mutations. Our study indicates that hormone castration is responsible for genomic instability generating new cytogenetic abnormalities susceptible to alter the properties of cancer cell associated with tumor progression, such as increased cell survival and ability to metastasize.
Legrier
Marie-Emmanuelle
ME
Institut Curie, Laboratoire d'Investigation Préclinique, Translational Research Department, Quadrilatère Historique porte 13, Hôpital Saint-Louis, Paris, France.
Guyader
Charlotte
C
Céraline
Jocelyn
J
Dutrillaux
Bernard
B
Oudard
Stéphane
S
Poupon
Marie-France
MF
Auger
Nathalie
N
D000818:Animals; D002869:Chromosome Aberrations; D002871:Chromosome Banding; D055028:Comparative Genomic Hybridization; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics
C410798:AR protein, human; D011944:Receptors, Androgen