title: Estrogen receptor potentiates mTORC2 signaling in breast cancer cells by upregulating superoxide anions.
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.
authors.affiliation: Division of Toxicology, Central Drug Research Institute (CSIR), India.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Kumari Kanchan
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Tripathi
authors.forename: Khemraj
authors.initials: K
authors.lastname: Singh Baghel
authors.forename: Shailendra
authors.initials: S
authors.lastname: Kumar Dwivedi
authors.forename: Balawant
authors.initials: B
authors.lastname: Kumar
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Sanyal
authors.forename: Sharad
authors.initials: S
authors.lastname: Sharma
authors.forename: Kalyan
authors.initials: K
authors.lastname: Mitra
authors.forename: Vivek
authors.initials: V
authors.lastname: Garg
authors.forename: Kavita
authors.initials: K
authors.lastname: Singh
authors.forename: Sarwat
authors.initials: S
authors.lastname: Sultana
authors.forename: Raj
authors.initials: R
authors.lastname: Kamal Tripathi
authors.forename: Srikanta
authors.initials: S
authors.lastname: Kumar Rath
authors.forename: Smrati
authors.initials: S
authors.lastname: Bhadauria
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D000076225:Mechanistic Target of Rapamycin Complex 2; D008928:Mitochondria / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D010084:Oxidation-Reduction; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D013481:Superoxides; D004958:Estradiol; D013482:Superoxide Dismutase; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases