Psychological stress induces chemoresistance in breast cancer by upregulating mdr1.
Psychological distress reduces the efficacy of chemotherapy in breast cancer patients. The mechanism may be related to the altered neuronal or hormonal secretions during stress. Here, we reported that adrenaline, a hormone mediating the biological activities of stress, upregulates mdr1 gene expression in MCF-7 breast cancer cells via alpha(2)-adrenergic receptors in a dose-dependent manner. Mdr1 upregulation can be specifically inhibited by pretreatment with mdr1-siRNA. Consequently, adrenergic stimulation enhances the pump function of P-glycoprotein and confers resistance of MCF-7 cells to paclitaxel. In vivo, restraint stress increases mdr1 gene expression in the MCF-7 cancers that are inoculated subcutaneously into the SCID mice and provokes resistance to doxorubicin in the implanted tumors. The effect can be blocked by injection of yohimbine, an alpha(2)-adrenergic inhibitor, but not by metyrapone, a corticosterone synthesis blocker. Therefore, we conclude that breast cancers may develop resistance against chemotherapeutic drugs under psychological distress by over-expressing mdr1 via adrenergic stimulation.
Su
Fengxi
F
Department of Breast Surgery, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, PR China.
Ouyang
Nengyong
N
Zhu
Pengcheng
P
Ouyang
Nengtai
N
Jia
Weijuan
W
Gong
Chang
C
Ma
Xuexia
X
Xu
Huanbin
H
Song
Erwei
E
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D017239:Paclitaxel; D004837:Epinephrine