Journal
ONCOTARGET
Volume 8, Issue 63, Pages 107134-107148Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.22359
Keywords
estrogen receptor; miR-1271; letrozole; DDIT3; breast cancer
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Attenuation of estrogen receptor alpha (ER alpha) expression via unknown mechanism(s) is a hallmark of endocrine-resistant breast cancer (BCa) progression. Here, we report that miR-1271 was significantly down-regulated in letrozole-resistant BCa tissues and in letrozole-resistant BCa cells. miR-1271 directly targeted the chromatin of DNA damage-inducible transcript 3 (DDIT3) gene. miR-1271 expression level was inversely correlated to DDIT3 mRNA level in BCa biopsies. Form a mechanistic standpoint, reintroduction of exogenous miR-1271 could effectively restore ER alpha level via inhibiting DDIT3 expression, thereby potentiating letrozole sensitivity in BCa cells. Moreover, DDIT3 deregulation promoted letrozole-resistance by acting as a potent corepressor of ESR1 transcription. Taken together, we have identified that disruption of the miR-1271/DDIT3/ER alpha cascade plays a causative role in the pathogenesis of letrozole resistance in BCa.
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