Estrogen receptor potentiates mTORC2 signaling in breast cancer cells by upregulating superoxide anions
Authors: Kalyan Mitra
Balawant Kumar
Srikanta Kumar Rath
Kavita Singh
Sarwat Sultana
Chakrapani Tripathi
Vivek Garg
Shailendra Kumar Dwivedi
Sharad Sharma
Sabyasachi Sanyal
Khemraj Singh Baghel
Raj Kamal Tripathi
Ranjana Kumari Kanchan
Smrati Bhadauria
Journal: Free Radical Biology and Medicine (2012)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Estrogen receptor; Breast cancer; Reactive oxygen species; Redox alterations; mTORC2
Affiliations: Division of Toxicology, Central Drug Research Institute (CSIR), India.

Abstract:  The estrogen receptor (ER) plays a cardinal role in estrogen-responsive breast carcinogenesis. It is, however, unclear as to how estrogen-ER interaction potentiates breast cancer progression. Compelling evidence supports estrogen-induced redox alterations, such as augmented reactive oxygen species (ROS) levels, as having a crucial role in breast carcinogenesis. Despite ER being a biological mediator of the majority of estrogen-induced cellular responses; its role in estrogen-induced tissue-specific ROS generation remains largely debatable. We examined a panel of human breast cancer specimens and found that ER-positive breast cancer specimens exhibited a higher incidence of augmented O(2)(•-) levels compared to matched normal tissue. ROS are known to function as signal transducers and ROS-mediated signaling remains a key complementary mechanism that drives carcinogenesis by activating redox-sensitive oncogenic pathways. Additional studies revealed that augmented O(2)(•-) levels in breast cancer specimens coincided with mammalian target of rapamycin complex 2 (mTORC2) hyperactivation. Detailed investigations using in vitro experiments established that 17β-estradiol (E2)-stimulated breast cancer cells exhibited transiently upregulated O(2)(•-) levels, with the presence of ER being a crucial determinant for the phenomenon to take place. Gene expression, ER transactivation, and confocal studies revealed that the E2-induced transient O(2)(•-) upregulation was effected by ER through a nongenomic pathway possibly involving mitochondria. Furthermore, E2 treatment activated mTORC2 in breast cancer cells in a characteristically ER-dependent manner. Interestingly, altering O(2)(•-) anion levels through chemical/genetic methods caused significant modulation of the mTORC2 signaling cascade. Taken together, our findings unravel a novel nongenomic pathway unique to estrogen-responsive breast cancer cells wherein, upon stimulation by E2, ER may regulate mTORC2 activity in a redox-dependent manner by transiently modulating O(2)(•-) levels particularly within mitochondria. The findings suggest that therapies aimed at counteracting these redox alterations and/or resultant signaling cascades may complement conventional treatments for estrogen-responsive breast cancer. 

Retracted: No

PubPeer comments:
 ![](http: ) ![file] , 
 Certainly a mistake. Thanks for identifying. Indeed by mistake we uploaded 0.25 (15 minutes) time point image at 0.5 min (30 minutes) time point as well. Both the images were part of same experiment, same concentration, only the different time point. This duplication was in advert ant and not done to mislead or change the conclusion. It was an unintentional and honest mistake that occurred during revision and editing. The correct figure is being uploaded. the correction does not change the conclusion of the study as there was no time dependent increase in given parameter following estrogen exposure of MDA-MB-231 cells.![file] , 
 #2 Is there an update on this correction? ,