Azariadis Kalliopi, Kiagiadaki Fotini, Pelekanou Vasiliki, Bempi Vasiliki, Alexakis Kostas, Kampa Marilena, Tsapis Andreas, Castanas Elias, Notas George
Laboratory of Experimental Endocrinology University of Crete School of Medicine, Heraklion, Greece.
Present affiliation: Department of Internal Medicine, University Hospital of Larissa, Larissa, Greece.
Cell Physiol Biochem. 2017;44(1):66-84. doi: 10.1159/000484584. Epub 2017 Nov 3.
BACKGROUND/AIMS: Reports regarding the role of androgen in breast cancer (BC) are conflicting. Some studies suggest that androgen could lead to undesirable responses in the presence of certain BC tumor characteristics. We have shown that androgen induces C-X-C motif chemokine 12 (CXCL12) in BC cell lines. Our aim was to identify the mechanisms regulating the phenotypic effects of androgen-induced CXCL12 on Androgen Receptor (AR) positive BC cell lines.
We analyzed the expression of CXCL12 and its receptors with qPCR and ELISA and the role of Nuclear Receptor Coactivator 1 (NCOA1) in this effect. AR effects on the CXCL12 promoter was studied via Chromatin-immunoprecipitation. We also analyzed publically available data from The Cancer Genome Atlas to verify AR-CXCL12 interactions and to identify the effect or Aromatase Inhibitors (AI) therapy on CXCL12 expression and disease progression in AR positive cases.
CXCL12 induction occurs only in AR-positive BC cell lines, possibly via an Androgen Response Element, upstream of the CXCL12 promoter. The steroid receptor co-regulator NCOA1 is critical for this effect. Androgen only induced the motility of p53-mutant BC cells T47D cells via upregulation of CXCR4 expression while they had no effect on wild-type p53 MCF-7 cells. Loss of CXCR4 expression and depletion of CXCL12 abolished the effect of androgen in T47D cells while inhibition of p53 expression in MCF-7 cells made them responsive to androgen and increased their motility in the presence to androgen. Patients with estrogen receptor positive (ER+)/AR+ BC treated with AIs were at increased risk of disease progression compared to ER+/AR+ non-AI treated and ER+/AR- AI treated cases.
AIs may lead to unfavorable responses in some ER/AR positive BC cases, especially in patients with AR+, p53 mutant tumors.
背景/目的：关于雄激素在乳腺癌（BC）中作用的报道相互矛盾。一些研究表明，在某些BC肿瘤特征存在的情况下，雄激素可能导致不良反应。我们已经证明，雄激素可在BC细胞系中诱导C-X-C基序趋化因子12（CXCL12）。我们的目的是确定调节雄激素诱导的CXCL12对雄激素受体（AR）阳性BC细胞系表型效应的机制。
我们通过qPCR和ELISA分析了CXCL12及其受体的表达，以及核受体辅激活因子1（NCOA1）在此效应中的作用。通过染色质免疫沉淀研究AR对CXCL12启动子的影响。我们还分析了来自癌症基因组图谱的公开数据，以验证AR-CXCL12相互作用，并确定芳香化酶抑制剂（AI）治疗对AR阳性病例中CXCL12表达和疾病进展的影响。
CXCL12的诱导仅发生在AR阳性的BC细胞系中，可能是通过CXCL12启动子上游的雄激素反应元件。类固醇受体共调节因子NCOA1对这种效应至关重要。雄激素仅通过上调CXCR4表达诱导p53突变的BC细胞T47D细胞的运动性，而对野生型p53的MCF-7细胞没有影响。CXCR4表达的缺失和CXCL12的消耗消除了雄激素在T47D细胞中的作用，而抑制MCF-7细胞中的p53表达使它们对雄激素有反应，并在存在雄激素的情况下增加了它们的运动性。与未接受AI治疗的ER+/AR+和接受AI治疗的ER+/AR-病例相比，接受AI治疗的雌激素受体阳性（ER+）/AR+ BC患者疾病进展风险增加。
AI可能在一些ER/AR阳性的BC病例中导致不良反应，尤其是在AR+、p53突变肿瘤的患者中。
