Skip Navigation


Carcinogenesis Advance Access originally published online on May 14, 2009
Carcinogenesis 2009 30(8):1298-1304; doi:10.1093/carcin/bgp120
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
30/8/1298    most recent
bgp120v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by LaPensee, E. W.
Right arrow Articles by Ben-Jonathan, N.
PubMed
Right arrow PubMed Citation
Right arrow Articles by LaPensee, E. W.
Right arrow Articles by Ben-Jonathan, N.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Prolactin confers resistance against cisplatin in breast cancer cells by activating glutathione-S-transferase

Elizabeth W. LaPensee, Sandy J. Schwemberger1, Christopher R. LaPensee, El Mustapha Bahassi, Scott E. Afton2 and Nira Ben-Jonathan*

Department of Cancer and Cell Biology
1 Shriners Burns Institute
2 Department of Chemistry, University of Cincinnati, Cincinnati, OH 45267, USA

* To whom correspondence should be addressed. Nira Ben-Jonathan, Department of Cancer and Cell Biology, University of Cincinnati, 3125 Eden Avenue, Cincinnati, OH 45267-0521, USA. Tel: +1 513 558 4821; Fax: +1 513 558 4823; Email: nira.ben-jonathan{at}uc.edu

Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients. Given that prolactin (PRL) acts as an anti-apoptotic/survival factor in the breast, we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs. Treatment of breast cancer cells with PRL caused variable resistance to taxol, vinblastine, doxorubicin and cisplatin. PRL prevented cisplatin-induced G2/M cell cycle arrest and apoptosis. In the presence of PRL, significantly less cisplatin was bound to DNA, as determined by mass spectroscopy, and little DNA damage was seen by {gamma}-H2AX staining. PRL dramatically increased the activity of glutathione-S-transferase (GST), which sequesters cisplatin in the cytoplasm; this increase was abrogated by Jak and mitogen-activated protein kinase inhibitors. PRL upregulated the expression of the GSTµ, but not the {pi}, isozyme. A GST inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL. In conclusion, PRL confers resistance against cisplatin by activating a detoxification enzyme, thereby reducing drug entry into the nucleus. These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer, which is characterized by high expression of both PRL and its receptor. Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options.

Abbreviations: CSS, charcoal-stripped serum; GST, glutathione-S-transferase; MAPK, mitogen-activated protein kinase; MRP, multidrug resistance-associated protein; 468, MDA-MB-468; PI, propidium iodide; PI3K, phosphoinositide-3 kinase; PRL, prolactin; PRL-R, prolactin receptor

Received February 6, 2009; revised May 1, 2009; accepted May 8, 2009.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.