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National Institute of Environmental Health Sciences

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Publication Detail

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

Authors: LaPensee, Elizabeth W; Schwemberger, Sandy J; LaPensee, Christopher R; Bahassi, El Mustapha; Afton, Scott E; Ben-Jonathan, Nira

Published In Carcinogenesis, (2009 Aug)

Abstract: 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 G(2)/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 GSTmu, 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.

PubMed ID: 19443905 Exiting the NIEHS site

MeSH Terms: Antibiotics, Antineoplastic/pharmacology; Antineoplastic Agents, Phytogenic/pharmacology; Antineoplastic Agents/therapeutic use*; Apoptosis/drug effects; Blotting, Western; Breast Neoplasms/drug therapy*; Breast Neoplasms/enzymology*; Breast Neoplasms/pathology; Cell Cycle/drug effects; Cell Nucleus/metabolism; Cisplatin/therapeutic use*; Cytoplasm/metabolism; Doxorubicin/pharmacology; Drug Resistance, Neoplasm*; Enzyme Activation/drug effects; Female; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; Glutathione Transferase/metabolism*; Glutathione/metabolism; Histones/metabolism; Humans; Paclitaxel/pharmacology; Prolactin/pharmacology*; RNA, Messenger/genetics; RNA, Messenger/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/drug effects; Tumor Cells, Cultured; Vinblastine/pharmacology

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