Chronic morphine treatment attenuates cell growth of human BT474 breast cancer cells by rearrangement of the ErbB signalling network
Authors: Inka Regine Weingaertner
Sarah Koutnik
Hermann Ammer
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: opioid analgesics; tumour growth; receptor tyrosine kinase; ERK1/2; Akt signalling
Affiliations: Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany.

Abstract:  Background: There is increasing evidence that opioid analgesics may interfere with tumour growth. It is currently thought that these effects are mediated by transactivation of receptor tyrosine kinase (RTK)-controlled ERK1/2 and Akt signalling. The growth of many breast cancer cells is dependent on hyperactive ErbB receptor networks and one of the most successful approaches in antineoplastic therapy during the last decade was the development of ErbB-targeted therapies. However, the response rates of single therapies are often poor and resistance mechanisms evolve rapidly. To date there is no information about the ability of opioid analgesics to interfere with the growth of ErbB-driven cancers. Methods and principal findings: Here we demonstrate that ErbB2 overexpressing BT474 human breast cancer cells carry fully functional endogenous ¬µ-opioid receptors. Most interestingly, the acute opioid effects on basal and Heregulin-stimulated ERK1/2 and Akt phosphorylation changed considerably during chronic Morphine treatment. Investigation of the underlying mechanism by the use of protein kinase inhibitors and co-immunoprecipitation studies revealed that chronic Morphine treatment results in rearrangement of the ErbB signalling network leading to dissociation of ERK1/2 from Akt signalling and a switch from ErbB1/ErbB3 to ErbB1/ErbB2-dependent cell growth. In chronically Morphine-treated cells Heregulin-stimulated ERK1/2 signalling is redirected via a newly established PI3K- and metalloproteinase-dependent feedback loop. Together, these alterations result in apoptosis of BT474 cells. A similar switch in Heregulin-stimulated ERK1/2 signalling from an ErbB2-independent to an ErbB2-, PI3K- and metalloproteinase-dependent mechanism was also observed in Œ∫-opioid receptor expressing SKBR3 human mammary adenocarcinoma cells. Conclusions and significance: The present data demonstrate that the ErbB receptor network of human breast cancer cells represents a target for chronic Morphine treatment. Rearrangement of ErbB signalling by chronic Morphine may provide a promising strategy to enhance the sensitivity of breast cancer cells to ErbB-directed therapies and to prevent the development of escape mechanisms. 

Retracted: No

PubPeer comments:
 Two corrections have been issued for this paper. The October 9, 2015 correction reads: (from: https: journals.plos.org plosone article?id=10.1371 journal.pone.0140727) *There is an undisclosed splice in Figure 1C in the published paper. In order to provide a clearer version of Figure 1C, the authors cropped the original image of the gel and spliced in a reformatted version of the 3rd AC type lane. The uncropped, original image of the gel is provided here as S1 Image. Additionally, there is an error in Fig 2B. The  control panel and  Heregulin + Morphine panel are mistakenly from the same sample. The authors have provided a correct version of Fig 2, which includes a new image for the  control panel. The uncropped samples for Fig 2B are provided here as S2 Image.* The April 14, 2016 correction reads: (from: https: journals.plos.org plosone article?id=10.1371 journal.pone.0153824) *There are undisclosed splices between lanes 2 and 3 for each panel in Fig 4A. Because no acute opioid effect on Akt phosphorylation was observed in nau00efve cells, the authors spliced out the Naloxone control band in order to save space. The authors have provided a corrected version of Fig 4, in which all splices are clearly demarcated with a vertical black line. The raw blots for each panel in Fig 4A are provided below as supporting information. Additionally, there is an error in Fig 5A that was introduced during figure preparation. In the right half of Fig 5A, the lowest control panel is erroneously a duplicate of the first two lanes of the lower control panel in Fig 4A. The authors have provided a corrected version of Fig 5. The raw blots for Fig 5A are provided below as supporting information.* , 
 Here is the original Figure 1C, with the undisclosed splice in lane 3:  Here is the original Figure 2B, with the overlapping two panels marked with red boxes:  Here is a comparison of Figure 4A and 5A with the duplicated panels marked with blue boxes:  ,