title: Estrogen suppresses breast cancer proliferation through GPER / p38 MAPK axis during hypoxia.
abstract: Breast cancer cells frequently experience hypoxia which is associated with resistance to hormonal therapy and poor clinical prognosis, making it important to understand the function of estrogen under hypoxic condition. Here, we demonstrate that estrogen suppresses breast cancer cell growth under hypoxia, through inhibition at G1/S phase of cell cycle, by elevation of p21 expression. The involvement of GPER in estrogen mediated growth arrest was elucidated using specific ligands and siRNA. Although, estrogen was observed to activate both p44/42 and p38 MAPK signaling, pharmacological inhibition and silencing of p38 MAPK abrogated the induction of p21 expression and growth arrest, during hypoxia. The involvement of estrogen induced ROS in the p38 MAPK mediated p21 expression and cell growth arrest was established by observing that scavenging of ROS by NAC abrogated p38 MAPK activation and p21 expression during hypoxia. In conclusion, Estrogen suppresses breast cancer growth by inhibiting G1/S phase transition through GPER/ROS/p38 MAPK/p21 mediated signaling during hypoxic condition.
authors.affiliation: Centre for Biotechnology, Anna University, Chennai, India.
authors.forename: S
authors.initials: S
authors.lastname: Sathya
authors.affiliation: Centre for Biotechnology, Anna University, Chennai, India.
authors.forename: S
authors.initials: S
authors.lastname: Sudhagar
authors.affiliation: Centre for Biotechnology, Anna University, Chennai, India; Centre for Food Technology, Anna University, Chennai, India. Electronic address: lakshmibs@annauniv.edu.
authors.forename: B S
authors.initials: BS
authors.lastname: Lakshmi
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004967:Estrogens; C109584:GPER1 protein, human; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled
keywords: Breast cancer; Cell cycle; Estrogen; GPER; Hypoxia; p21; p38 MAPK