title: EGFR/HER2 inhibitors effectively reduce the malignant potential of MDR breast cancer evoked by P-gp substrates in vitro and in vivo.
abstract: Multidrug resistance (MDR) induced by chemotherapy in breast cancer frequently leads to tumor invasion, metastasis and poor clinical outcome. We preliminarily found that the epidermal growth factor receptor (EGFR) is involved in enhancing the malignant potential of MDR breast cancer cells, but the mechanism remains unclear. In the present study, we demonstrated in vitro and in vivo that EGFR/HER2 promote the invasive and metastatic abilities of MDR breast cancer. More importantly, a new function of EGFR/HER2 inhibitors was revealed for the first time, which could improve the treatment efficacy of breast cancer by reversing the MDR process rather than by inhibiting tumor growth. Firstly, using quantitative real‑time PCR and western blot analysis, we found that overexpression of EGFR/HER2 in MCF7/Adr cells upregulated CD147 and MMP2/9 at both the transcription and protein expression levels, which promoted tumor cell migration, as determined using an in vitro invasion assay. Secondly, the upregulated levels of CD147 and MMP2/9 were decreased when EGFR/HER2 activity was inhibited, and therefore tumor invasion was also significantly inhibited. These phenomena were also demonstrated in nude mouse assays. Additionally, in MDR breast cancer patients, we found that overexpression of EGFR and P‑gp levels led to shorter overall survival (OS) and disease‑free survival (DFS) by IHC assays and Kaplan‑Meier survival analysis. In conclusion, EGFR/HER2 play a crucial role in enhancing CD147 and MMP expression to establish favorable conditions for invasion/metastasis in MDR breast cancer. The scope of application of EGFR/HER2 inhibitors may be expanded in EGFR/HER2‑positive patients. We suggest that MDR breast cancer patients may benefit from novel therapies targeting EGFR/HER2.
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200240, P.R. China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200240, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200240, P.R. China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200240, P.R. China.
authors.forename: Zijing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200240, P.R. China.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Chu
authors.affiliation: Department of Pathology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200240, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human