Silencing MED1 sensitizes breast cancer cells to pure anti-estrogen fulvestrant in vitro and in vivo.
Pure anti-estrogen fulvestrant has been shown to be a promising ER antagonist for locally advanced and metastatic breast cancer. Unfortunately, a significant proportion of patients developed resistance to this type of endocrine therapy but the molecular mechanisms governing cellular responsiveness to this agent remain poorly understood. Here, we've reported that knockdown of estrogen receptor coactivator MED1 sensitized fulvestrant resistance breast cancer cells to fulvestrant treatment. We found that MED1 knockdown further promoted cell cycle arrest induced by fulvestrant. Using an orthotopic xenograft mouse model, we found that knockdown of MED1 significantly reduced tumor growth in mice. Importantly, knockdown of MED1 further potentiated tumor growth inhibition by fulvestrant. Mechanistic studies indicated that combination of fulvestrant treatment and MED1 knockdown is able to cooperatively inhibit the expression of ER target genes. Chromatin immunoprecipitation experiments further supported a role for MED1 in regulating the recruitment of RNA polymerase II and transcriptional corepressor HDAC1 on endogenous ER target gene promoter in the presence of fulvestrant. These results demonstrate a role for MED1 in mediating resistance to the pure anti-estrogen fulvestrant both in vitro and in vivo.
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Lijiang
L
Zhang
Jiajun
J
Cui
Marissa
M
Leonard
Kenneth
K
Nephew
Yongquan
Y
Li
Xiaoting
X
Zhang
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D056913:Mediator Complex Subunit 1 / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D000071163:Trefoil Factor-1; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D018931:Antineoplastic Agents, Hormonal; D020847:Estrogen Receptor Modulators; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D011960:Receptors, Estrogen; C051838:TFF1 protein, human; D000071163:Trefoil Factor-1; D025521:Tumor Suppressor Proteins; D000077267:Fulvestrant; D004958:Estradiol; D012319:RNA Polymerase II; D056284:Histone Deacetylase 1