Abstract
Estrogens have been implicated in the etiology of breast cancer for a long time. It has been stated that long-term exposure to estrogens is associated with a higher incidence of breast cancer, since estradiol (E2) stimulates breast cell growth; however, its effect on DNA damage/repair is only starting to be investigated. Recent studies have documented that estrogens are able to modify the DNA damage response (DDR) and DNA repair mechanisms. On the other hand, it has been proposed that DDR machinery can be altered by estrogen signaling pathways, that can be related to cancer progression and chemoresistance. We have demonstrated that E2 promotes c-Src activation and breast cancer cell motility, through a non-genomic pathway. This review discusses scientific evidence supporting this non-genomic mechanism where estrogen modifies the DNA repair pathways, and its relationship to potential causes of chemoresistance.
Highlights
The role of estrogens in the onset of breast cancer, its progression in early stages of the disease, and during invasion, has long been demonstrated [1, 2]
Another proposed mechanism is that mER-E2 complex inhibits the activation of Chk1, a Ser/Thr kinase that is required for cell cycle arrest, since it is activated at checkpoints in response to DNA damage
G Protein-coupled Estrogen Receptor (GPER) mechanism starts it binds to E2, inducing conformational changes that activates the trimeric G-protein that is coupled to the receptor, which induces the activation of cSrc kinase and the formation of the c-Src/PI3-K complex that favors the activation of Akt and PKCz pathways, where Akt increases the transcription of cyclin D1, and PKCz actives the Ras/Raf/MEK/ERK pathway, promoting the G1/S transition in cancer cells [66]
Summary
The role of estrogens in the onset of breast cancer, its progression in early stages of the disease, and during invasion, has long been demonstrated [1, 2]. It is well known that estrogens can induce non-genomic mechanisms, which do not require the translocation of the E2ER complex through the pore into the nucleus and, the ER can be anchored to the cell membrane, through reversible post-translational lipid modification that involves linkage of a fatty acid chain, so they are called membrane ER alpha and beta (mERa and mERb) [15,16,17,18,19,20] Those mER have been described in cellular organelles, such as the mitochondria, and different tissues including liver, muscle, fat, and the b-cell of the pancreas [20, 21]. There is evidence that even the simple activation of the transcription factor SNAIL1 can induce transcriptional repression of ERa, demonstrating the importance of its loss in breast cancer, which correlates with poor prognosis, increased recurrence after treatment and increased incidence of metastasis [31, 32]
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