PMID- 26411365 OWN - NLM STAT- MEDLINE DCOM- 20170828 LR - 20210514 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 35 IP - 22 DP - 2016 Jun 2 TI - Estrogen promotes the brain metastatic colonization of triple negative breast cancer cells via an astrocyte-mediated paracrine mechanism. PG - 2881-92 LID - 10.1038/onc.2015.353 [doi] AB - Brain metastases (BM) are a devastating consequence of breast cancer. BM occur more frequently in patients with estrogen receptor-negative (ER-) breast cancer subtypes; HER2 overexpressing (HER2+) tumors and triple-negative (TN) (ER-, progesterone receptor-negative (PR-) and normal HER2) tumors. Young age is an independent risk factor for the development of BM, thus we speculated that higher circulating estrogens in young, pre-menopausal women could exert paracrine effects through the highly estrogen-responsive brain microenvironment. Using a TN experimental metastases model, we demonstrate that ovariectomy decreased the frequency of magnetic resonance imaging-detectable lesions by 56% as compared with estrogen supplementation, and that the combination of ovariectomy and letrozole further reduced the frequency of large lesions to 14.4% of the estrogen control. Human BM expressed 4.2-48.4% ER+ stromal area, particularly ER+ astrocytes. In vitro, E2-treated astrocytes increased proliferation, migration and invasion of 231BR-EGFP cells in an ER-dependent manner. E2 upregulated epidermal growth factor receptor (EGFR) ligands Egf, Ereg and Tgfa mRNA and protein levels in astrocytes, and activated EGFR in brain metastatic cells. Co-culture of 231BR-EGFP cells with E2-treated astrocytes led to the upregulation of the metastatic mediator S100 Calcium-binding protein A4 (S100A4) (1.78-fold, P<0.05). Exogenous EGF increased S100A4 mRNA levels in 231BR-EGFP cells (1.40+/-0.02-fold, P<0.01 compared with vehicle control) and an EGFR/HER2 inhibitor blocked this effect, suggesting that S100A4 is a downstream effector of EGFR activation. Short hairpin RNA-mediated S100A4 silencing in 231BR-EGFP cells decreased their migration and invasion in response to E2-CM, abolished their increased proliferation in co-cultures with E2-treated astrocytes and decreased brain metastatic colonization. Thus, S100A4 is one effector of the paracrine action of E2 in brain metastatic cells. These studies provide a novel mechanism by which estrogens, acting through ER+ astrocytes in the brain microenvironment, can promote BM of TN breast cancers, and suggests existing endocrine agents may provide some clinical benefit towards reducing and managing BM. FAU - Sartorius, C A AU - Sartorius CA AD - Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. FAU - Hanna, C T AU - Hanna CT AD - Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. FAU - Gril, B AU - Gril B AD - Women's Malignancies Branch, National Cancer Institute, Bethesda, MD, USA. FAU - Cruz, H AU - Cruz H AD - Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. FAU - Serkova, N J AU - Serkova NJ AD - Department of Anesthesiology, University of Colorado Denver, Anschutz Medical, Aurora, CO, USA. FAU - Huber, K M AU - Huber KM AD - Department of Anesthesiology, University of Colorado Denver, Anschutz Medical, Aurora, CO, USA. FAU - Kabos, P AU - Kabos P AD - Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. FAU - Schedin, T B AU - Schedin TB AD - Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. FAU - Borges, V F AU - Borges VF AD - Department of Medicine, Division of Medical Oncology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. FAU - Steeg, P S AU - Steeg PS AD - Women's Malignancies Branch, National Cancer Institute, Bethesda, MD, USA. FAU - Cittelly, D M AU - Cittelly DM AD - Department of Pathology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. LA - eng GR - K08 CA164048/CA/NCI NIH HHS/United States GR - R01 CA140985/CA/NCI NIH HHS/United States GR - P30 CA046934/CA/NCI NIH HHS/United States GR - UL1 TR001082/TR/NCATS NIH HHS/United States GR - K22 CA181250/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20150928 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (Estrogens) RN - 4TI98Z838E (Estradiol) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Animals MH - Astrocytes/drug effects/*pathology MH - Brain Neoplasms/*secondary MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Cell Transformation, Neoplastic MH - ErbB Receptors/metabolism MH - Estradiol/pharmacology MH - Estrogens/*metabolism MH - Gene Knockdown Techniques MH - Humans MH - Mice MH - Mice, Nude MH - Neoplasm Invasiveness MH - *Paracrine Communication/drug effects MH - Triple Negative Breast Neoplasms/*pathology PMC - PMC4809801 MID - NIHMS716607 EDAT- 2015/09/29 06:00 MHDA- 2017/08/29 06:00 PMCR- 2016/07/08 CRDT- 2015/09/29 06:00 PHST- 2015/04/01 00:00 [received] PHST- 2015/07/21 00:00 [revised] PHST- 2015/08/17 00:00 [accepted] PHST- 2015/09/29 06:00 [entrez] PHST- 2015/09/29 06:00 [pubmed] PHST- 2017/08/29 06:00 [medline] PHST- 2016/07/08 00:00 [pmc-release] AID - onc2015353 [pii] AID - 10.1038/onc.2015.353 [doi] PST - ppublish SO - Oncogene. 2016 Jun 2;35(22):2881-92. doi: 10.1038/onc.2015.353. Epub 2015 Sep 28.