Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells
Authors: Raphaële Buser
Laurence Lesne
Pierre Maechler
Frédérique Béna
Vincent Favaudon
André-Pascal Sappino
Christelle Stouder
Stefano J Mandriota
Curzio Rüegg
Virginie Clément
Roberto Montesano
Journal: Journal of Biological Chemistry (2010)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: ATM; breast cancer; cell cycle checkpoint; genomic instability; cellular transformation
Affiliations: Center of Oncology, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland. 

Abstract:  Carriers of mutations in the cell cycle checkpoint protein kinase ataxia telangiectasia mutated (ATM), which represent 1-2% of the general population, have an increased risk of breast cancer. However, experimental evidence that ATM deficiency contributes to human breast carcinogenesis is lacking. We report here that in MCF-10A and MCF-12A cells, which are well established normal human mammary gland epithelial cell models, partial or almost complete stable ATM silencing or pharmacological inhibition resulted in cellular transformation, genomic instability, and formation of dysplastic lesions in NOD/SCID mice. These effects did not require the activity of exogenous DNA-damaging agents and were preceded by an unsuspected and striking increase in cell proliferation also observed in primary human mammary gland epithelial cells. Increased proliferation correlated with a dramatic, transient, and proteasome-dependent reduction of p21(WAF1/CIP1) and p27(KIP1) protein levels, whereas little or no effect was observed on p21(WAF1/CIP1) or p27(KIP1) mRNAs. p21(WAF1/CIP1) silencing also increased MCF-10A cell proliferation, thus identifying p21(WAF1/CIP1) down-regulation as a mediator of the proliferative effect of ATM inhibition. Our findings provide the first experimental evidence that ATM is a human breast tumor suppressor. In addition, they mirror the sensitivity of ATM tumor suppressor function and unveil a new mechanism by which ATM might prevent human breast tumorigenesis, namely a direct inhibitory effect on the basal proliferation of normal mammary epithelial cells. 

Retracted: No

PubPeer comments:
 ACE2 is the receptor for SARS-CoV and SARS-CoV2 so we need to understand ACE2u2019s cellular function, given that we are in the middle of the COVID-19 pandemic. It is, therefore, a tad vexatious to see that three western blot lanes are reused and reordered in the very first image shown in Fig. 1A of this ACE2 cellular function paper. ![image] , 
 An erratum for the WB reuse in Fig. 1 has now been published (14-9-2021). https: pubmed.ncbi.nlm.nih.gov 34521972 *u201cThis Article contains errors.* *For Figureu00a01A, lanes 1u20133 were inadvertently duplicated for lanes 10u201312. In addition, it was not clearly indicated in the original Figure that this image was a composite. A corrected version of Figureu00a01 and its figure legend appears below.u201d* In Fig. 6B, the second rightmost lane of p-ERK1 2 has been pasted into the WB. Itu2019s visible in the grey scale but contrast enhancement and FIJI LUT u2018smartu2019 might make the lane edges a bit clearer. ![image] , 
 When there is in-paper WB lane reusage, it can be informative to check whether there might be between-paper WB lane reuse too. There is but, for some mysterious reason, the lanes have been flipped vertically. The journal SHOCK owns the copyright to this image. ![image] , 
 There is yet another example of lane reusage in this Sci Rep article as taken from the earlier SHOCK offering. As it happens, this time with horizontal flippage ![image] ,