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

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.

Prolactin receptor in breast cancer: marker for metastatic risk

“…PRL and the long form of the PRLR also contribute to the metastatic process (Yonezawa et al 2015). These results are consistent with the reports of PRLR-mediated chemotherapeutic resistance (Howell et al 2008, LaPensee et al 2009) and the role of PRL-PRLR in osteolytic bone metastases of breast cancer cells (Sutherland et al 2016). The recent demonstration of PRL and PRLR mRNA and protein in tumor-initiating cells warrants additional follow-up, and their roles in apoptosis and sphere formation may indicate a contribution to early tumorigenesis, metastasis and chemotherapy resistance, consistent with the role of tumor-initiating cells in cancer.…”

Molecular Pathways: Blockade of the PRLR Signaling Pathway as a Novel Antihormonal Approach for the Treatment of Breast and Prostate Cancer

“…In addition to being a mitogen, PRL also has the capacity to inhibit cell death induced by cisplatin, doxorubicin, taxol, and other agents in cancer cells (53,54). Mechanistically, in breast cancer cells, this can occur through drug detoxification arising from PRL-induced activation of glutathione S-transferase (54) or potentially via PRL-mediated upregulation of antiapoptotic proteins such as Bcl-2 (55).…”

Induction of Multidrug Resistance Transporter ABCG2 by Prolactin in Human Breast Cancer Cells

“…In addition to its role in the biology of breast cancer progression, there is evidence that PRL can modulate the cytotoxicity of chemotherapeutic agents. PRL antagonists have been shown to enhance the cytotoxic effect of cisplatin, paclitaxel, and doxorubicin in breast cancer cell lines (Ramamoorthy et al, 2001;Howell et al, 2008), whereas pretreatment with PRL can attenuate the cytotoxicity of chemotherapeutic agents taxol, vinblastine, doxorubicin, and cisplatin (LaPensee et al, 2009). Our results suggest that PRL may confer resistance to such chemotherapeutics as doxorubicin by induction of ABCG2.…”