Editors' ChoiceCancer

Preserving Both Life and Fertility

Science Signaling  20 Oct 2009:
Vol. 2, Issue 93, pp. ec338
DOI: 10.1126/scisignal.293ec338

Young women diagnosed with cancer can face the agonizing realization that the very chemotherapeutic treatments required to save their lives may also destroy their fertility. Moreover, the ability of a particular individual to take advantage of cryopreservation techniques may be limited by the urgency with which she needs to start treatment or the possibility that the cancer has invaded the ovaries (see Perspective by Woodruff). Gonfloni et al. found that in vitro exposure of ovaries from 5-day-old mice to the chemotherapeutic agent cisplatin led to increased abundance of the TAp63-α isoform of the p63 tumor suppressor in ovarian lysates, DNA double-strand breaks, and massive oocyte apoptosis. Cisplatin also increased the abundance of the mRNA encoding the c-Abl tyrosine kinase, as well as c-Abl protein, and inhibition of c-Abl with imatinib blocked not only the increase in c-Abl mRNA but also the increase in TAp63 and apoptosis. Experiments in a human osteosarcoma cell line stably transfected with a construct that could be induced to express TAp63-α by tetracycline treatment revealed that cisplatin-induced apoptosis depended on TAp63-α. Constitutively active forms of c-Abl phosphorylated TAp63 and increased its abundance; mutational analysis implicated one of these phosphorylated residues (Tyr149) in the ability of TAp63 to transcriptionally induce the proapoptotic proteins NOXA and PUMA. Intraperitoneal injection of cisplatin into female mouse pups led to depletion of primordial and primary ovarian follicles, an effect that was substantially attenuated by coinjection of imatinib. Moreover, imatinib partially rescued cisplatin-induced infertility. Thus, the authors have identified a pathway involved in oocyte loss in response to cisplatin and shown that imatinib has a fertoprotective effect. Whether imatinib also interferes with cisplatin’s antineoplastic effect remains to be determined.

S. Gonfloni, L. Di Tella, S. Caldarola, S. M. Cannata, F. G. Klinger, C. Di Bartolomeo, M. Mattei, E. Candi, M. De Felici, G. Melino, G. Cesareni, Inhibition of the c-Abl–TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nat. Med. 15, 1179–1185 (2009). [PubMed]

T. K. Woodruff, Preserving fertility during cancer treatment. Nat. Med. 15, 1124–1125 (2009). [PubMed]