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Estrogen receptor ? regulates ATM Expression through miRNAs in breast cancer.

ABSTRACT: Estrogen receptor ? (ER?) is an essential element regulating mammary gland development and it contributes to breast cancer development and progression. Most of the ER-negative breast cancers display more aggressive clinical behaviors and are resistant to antiestrogen therapies. In addition, many ER-negative tumors show insensitivity to many chemotherapeutic drugs and radiotherapy, although mechanisms underlying this phenotype are less clear.We conducted immunohistochemistry on 296 cases of breast cancer tissues using a variety of antibodies. On the basis of the clinical data, we conducted siRNA knockdown to study the role of ER? on ATM expression in breast cancer cell lines. Furthermore, we used antisense oligonucleotides against micro RNAs (miRNA) or miRNA overexpression plasmids to study the role of miR-18a and -106a on ATM expression. Finally we used in situ hybridization to assess miR-18a and -106a expression in breast cancer tissues.We found that in ER-negative breast cancer tissues, expression of the ATM kinase, a critical DNA damage-response protein, is aberrantly upregulated. We also found that the locoregional recurrence rate after radiotherapy positively correlates with ATM expression. On the cellular level, we showed that ER?, but not ER?, negatively regulates ATM expression. Furthermore, we identified that ER? activates miR-18a and -106a to downregulate ATM expression. We also showed that miR-18a and -106a were significantly underexpressed in ER-negative breast cancer tissues.We reveal a novel mechanism involving ER? and miR-18a and -106a regulation of ATM in breast cancer.

SUBMITTER: Guo X

PROVIDER: S-EPMC3778106 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Estrogen receptor α regulates ATM Expression through miRNAs in breast cancer.

Guo Xiaojing X Yang Chunying C Qian Xiaolong X Lei Ting T Li Yaqing Y Shen Haifa H Fu Li L Xu Bo B

Clinical cancer research : an official journal of the American Association for Cancer Research 20130715 18

<h4>Purpose</h4>Estrogen receptor α (ERα) is an essential element regulating mammary gland development and it contributes to breast cancer development and progression. Most of the ER-negative breast cancers display more aggressive clinical behaviors and are resistant to antiestrogen therapies. In addition, many ER-negative tumors show insensitivity to many chemotherapeutic drugs and radiotherapy, although mechanisms underlying this phenotype are less clear.<h4>Experimental design</h4>We conducte ...[more]

PMID: 23857602

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Project description:Fatty acid synthase (FASN), the key enzyme for endogenous synthesis of fatty acids, is overexpressed and hyperactivated in a biologically aggressive subset of sex steroid-related tumors, including breast carcinomas. Using pharmacological and genetic approaches, we assessed the molecular relationship between FASN signaling and estrogen receptor alpha (ER?) signaling in breast cancer. The small compound C75, a synthetic slow-binding inhibitor of FASN activity, induced a dramatic augmentation of estradiol (E2)-stimulated, ER?-driven transcription. FASN and ER? were both necessary for the synergistic activation of ER? transcriptional activity that occurred following co-exposure to C75 and E2: first, knockdown of FASN expression using RNAi (RNA interference) drastically lowered (>100 fold) the amount of E2 required for optimal activation of ER?-mediated transcriptional activity; second, FASN blockade synergistically increased E2-stimulated ER?-mediated transcriptional activity in ER?-negative breast cancer cells stably transfected with ER?, but not in ER?-negative parental cells. Non-genomic, E2-regulated cross-talk between the ER? and MAPK pathways participated in these phenomena. Thus, treatment with the pure antiestrogen ICI 182?780 or the potent and specific inhibitor of MEK/ERK, U0126, was sufficient to abolish the synergistic nature of the interaction between FASN blockade and E2-stimulated ER? transactivation. FASN inhibition suppressed E2-stimulated breast cancer cell proliferation and anchorage-independent colony formation while promoting the reduction of ER? protein. FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1, two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E2-promoted anchorage-independent growth. The ability of FASN to regulate E2/ER? signaling may represent a promising strategy for anticancer treatment involving a new generation of FASN inhibitors.

Dataset Information

Estrogen receptor ? regulates ATM Expression through miRNAs in breast cancer.

Publications

Estrogen receptor α regulates ATM Expression through miRNAs in breast cancer.

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