Senescence sensitivity of breast cancer cells is defined by positive feedback loop between CIP2A and E2F1
Authors: Minna Niemel√§
Kevin M Ryan
Melissa R Junttila
Veli-Matti K√§h√§ri
Anchit Khanna
Gerard I Evan
Jukka Westermarck
Anni Laine
Edward K Chan
Heikki Joensuu
Pirkko-Liisa Kellokumpu-Lehtinen
Harri Sihto
Aleksandra Zwolinska
Christophe Come
Owen J Sansom
Mathias T Rosenfeldt
Jean-Christophe Marine
Journal: Cancer Discovery (2013)
Discipline: CLINICAL MEDICINE
Keywords: Senescence induction; p53; E2F1; CIP2A; PP2A
Affiliations: Turku Centre for Biotechnology, University of Turku and √Öbo Akademi University, Turku, Finland.

Abstract:  Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we show that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence show that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A-deficient mouse model, and CIP2A-deficient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of patients with breast cancer treated with senescence-inducing chemotherapy. Together, these results implicate the E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. This feedback loop also constitutes a promising prosenescence target for therapy of cancers with an inactivated p53-p21 pathway. Significance: It has been recently realized that most currently used chemotherapies exert their therapeutic effect at least partly by induction of terminal cell arrest, senescence. However, the mechanisms by which cell-intrinsic senescence sensitivity is determined are poorly understood. Results of this study identify the E2F1-CIP2A positive feedback loop as a key determinant of breast cancer cell sensitivity to senescence and growth arrest induction. Our data also indicate that this newly characterized interplay between 2 frequently overexpressed oncoproteins constitutes a promising prosenescence target for therapy of cancers with inactivated p53 and p21. Finally, these results may also facilitate novel stratification strategies for selection of patients to receive senescence-inducing cancer therapies. 

Retracted: No

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 This same pseudoname authors has left several similar comments on our papers during the past week. I would greatly appreciate if people would dare to use their own identity if they dare to publicly comment on other peopleu00b4s work. Related to comments themselves, they all seem to deal with cutting of unrelevant control information from between the lanes that contain the actual data. The other option would have been to rerun the blots and leave those unrelevant samples away but having about 70 blots in one paper that would have been enormous task with no additional benefit. So in case these pseudoname authors have any additional similar comments on our papers, I would encourage you to send your comments directly to me at jukwes@utu.fi, so we can discuss them openly. Thank you. Jukka Westermarck , 
 #6  they all seem to deal with cutting of unrelevant control information from between the lanes that contain the actual data. 1. Figure 7I in this paper is image duplication. 2. Splicing in some panels, but not in others is problematic. If lanes have been removed from some panels, but not other panels, the panels are unlikely to have come from the same blot. Loading controls are a claim that the panels come from the same blot.  send your comments directly to me at jukwes@utu.fi, so we can discuss them openly You can discuss them openly here. , 
 #6  Unrelevant control information ? Since when are controls irrelevant? At the very least the splices needed to be declared or depicted with a line. But the fact that the splicing seems to be inconsistent between different antibodies on what is supposed to be the same samples, is highly problematic. It suggests undeclared and poor use of replicate loadings at best and outright deception at worst. The Fig 7l duplication is particularly bad. , 
 #8  Since when are controls irrelevant? Control information is unrelevant for example if it is an additional concentration or treatment that does not have any impact on the conclusions.  But the fact that the splicing seems to be inconsistent between different antibodies on what is supposed to be the same samples, is highly problematic. It None of the blots have been cut inconsitently between different antibodies. It may appear like that as the border between cut pieces becomes visible only in some places whereas in some places because we have paid extra attention to make the blots to look as good as possible and fused the slices so that it is very difficult to see the border. An example of that is Fig. 2 F where cutting has been made for every blot from all 1d, 2d and 3d samples so all together 8 cuts but you can readily see only the one that is now pointed with an arrow.  At the very least the splices needed to be declared or depicted with a line. Every single figure legend states clearly that cuts have been made. For example Fig.2F  Irrelevant  data have been removed from the original graph. All this has gone through 3 rounds of very strict peer review and this strategy was approved by all three reviewers and the editor so I would really really appreciate if we could leave this issue here.  The Fig 7l duplication is particularly bad. This was a pure accident and does not change the conclusions as the actual result can be seen from the quantitation. However, we will replace the blot with the actual one and report to Cancer Discovery about the correction. No consequences to results or conclusions of the paper. Jukka Westermarck, jukwes@utu.fi , 
 #9  An example of that is Fig. 2 F where cutting has been made for every blot from all 1d, 2d and 3d samples so all together 8 cuts but you can readily see only the one that is now pointed with an arrow. What about 2D?  All this has gone through 3 rounds of very strict peer review and this strategy was approved by all three reviewers and the editor so I would really really appreciate if we could leave this issue here. Putting the cart before the horse. , 
 #10 What about 2D? Exactly the same case, each lane has been cut. I will leave this endless discussion here , 
 Could you post the full blots used to make the figures under question here? , 
 #9 Dr. Westermark, can you please explain what this means:  Control information is unrelevant for example if it is an additional concentration or treatment that does not have any impact on the conclusions. ? Also may I ask, are your loading controls always from the same gel as the rest of the figure? , 
 2020 correction. https: cancerdiscovery.aacrjournals.org content 10 5 746 In the original version of this article (1), in Fig. 7I the u03b2-actin bands shown as the loading control for lanes 1u20133 were inadvertently also presented as the loading controls for lanes 4u20136. This does not affect the quantified numbers below the original Western blot analysis, which were based on using the correct actin loading samples. Dotted lines to indicate joining of lanes that were not continuous in the original Western blots have also been added. The figure has been corrected in the latest online HTML and PDF versions of the article. The authors regret the error. , 
 Jukka Westermarck: Publications in which the role of CIP2A in senescence has been followed up: https: pubmed.ncbi.nlm.nih.gov ?term=cip2a+senescence sort=date Publications in which the role of CIP2A in senescence has been followed up: https: pubmed.ncbi.nlm.nih.gov ?term=cip2a+e2f1 sort=date Replication of the main findings of the study discussed here in dozens of follow-up papers should remove any remaining doubts about validity of the data. , 
 #15 The issue is the data in this paper. ,