Enforced expression of hsa-miR-125a-3p in breast cancer cells potentiates docetaxel sensitivity via modulation of BRCA1 signaling.
Epigenetic gene inactivation by microRNAs (miRNAs) plays a key role in malignant transformation, prevention of apoptosis, drug resistance and metastasis. It has been shown that miR-125a is down-regulated in HER2-amplified and HER2-overexpressing breast cancers (BCa), and this miRNA is believed to serve as an important tumor suppressor. miR-125a has two mature forms: hsa-miR-125a-3p and hsa-miR-125a-5p. However, the functional details of these miRNAs in BCa, particularly during pathogenesis of drug resistance, remain largely unexplored. Herein, we reported that hsa-miR-125a-3p expression was significantly reduced in chemoresistant BCa tissues and in experimentally established chemoresistant BCa cells. hsa-miR-125a-3p knockdown promoted cell proliferation and compromised docetaxel (Dox)-induced cell death, whereas overexpression of hsa-miR-125a-3p attenuated Dox chemoresistance in BCa cells. From a mechanistic standpoint, hsa-miR-125a-3p directly targeted 3'-untranslated regions (3'-UTRs) of breast cancer early onset gene 1 (BRCA1) and inhibits its protein expression via translational repression mechanism. In addition, suppression of BRCA1 expression by siRNA treatment effectively improved hsa-miR-125a-3p deficiency-triggered chemoresistance in BCa cells. Collectively, these findings suggest that hsa-miR-125a-3p may function as a tumor suppressor by regulating the BRCA1 signaling, and reintroduction of hsa-miR-125a-3p analogs could be a potential adjunct therapy for advanced/chemoresistant BCa.
Department of Thyroid Gland and Breast Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
Xin
X
Xu
Department of Thyroid Gland and Breast Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
Yong-Gang
YG
Lv
Xi'an Health Management Service Center, Xi'an 710032, Shaanxi Province, China.
Chang-You
CY
Yan
Department of Thyroid Gland and Breast Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: yijun1720@163.com.
Jun
J
Yi
Department of Thyroid Gland and Breast Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China. Electronic address: lingrui0105@163.com.
Rui
R
Ling
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D019398:Genes, BRCA1; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology*
D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm; D043823:Taxoids; D000077143:Docetaxel
BRCA1; Breast cancer; Chemoresistance; Docetaxel; miRNAs