Rapid non genomic signalling by 17ß estradiol through c Src involves mTOR dependent expression of HIF 1and#945; and modulates cellular energy homeostasis in breast cancer cells

Abstract

An increasing incidence of breast cancer is being observed in many developing countries, including India. The female steroid hormone estrogen regulates diverse physiological functions including cardiovascular health, inflammatory response, neural function, bone integrity and energy homeostasis in addition to playing a significant role in the development of pathological processes including breast cancer progression. This study demonstrates that exposure of human breast cancer lines to 17ß-estradiol (E2) rapidly induced the expression of HIF-1and#945;, the regulated subunit of HIF1, in normoxic condition through non-genomic signalling as well as modulating glucose uptake and cellular energy homeostasis. The results define a signalling pathway in breast cancer cells whereby estradiol induces a rapid protein protein interaction of ERand#945;- c-Src- PI3K, resulting in the activation of PI3K/AKT pathway leading to mammalian target of rapamycin (mTOR) phosphorylation and its downstream signalling, modulating HIF-1and#945; protein synthesis. In conclusion the present work demonstrates that 17ß-estradiol (E2), the most potent form of circulating oestrogen, stimulates steroid-starved ERand#945;-positive breast cancer cells by rapid accumulation of HIF-1and#945; and activates HIF1 through its non-genomic signalling. The estrogen induced HIF-1and#945; expression involves enhanced HIF-1and#945; translation mediated by mammalian target of rapamycin (mTOR) signalling. These data support a model of estrogen mediated HIF-1and#945; expression through ERand#945;/c- Src/PI3K/Akt/mTOR signalling pathway in breast cancer cells. Moreover, Estrogen enhances glucose uptake and energy utilization in cancer cells in addition to modulation of cellular energy metabolism providing a new understanding towards estrogen mediated altered cellular metabolism in newlinebreast cancer cells. newline newline newline