Nuclear TBLR1 as an ER corepressor promotes cell proliferation, migration and invasion in breast and ovarian cancer.
Estrogen receptors (ER) play important roles in the development and progression of breast and ovarian cancers. ERs mediate transcriptional regulation through interaction with cofactors and binding to response elements within the regulatory elements of target genes. Here, we examined the expression and function of TBLR1/TBL1XR1, a core component of NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid receptor) corepressor complexes, in breast and ovarian cancers. We found that although TBLR1 is present in both the nucleus and cytoplasm of normal and neoplastic breast and ovarian cells, it is expressed at significantly higher levels in the nucleus of malignant breast and ovarian cells compared to benign cells. TBLR1 functions as an ER corepressor to inhibit ER-mediated transcriptional activation in both breast and ovarian cell lines, but it has no effect on androgen receptor (AR) mediated transcriptional activation in these cells. Furthermore, ectopic expression of nuclear TBLR1 in breast and ovarian cancer cells stimulates cell proliferation. The increased cell proliferation by nuclear TBLR1 is through both ER-independent and ER-dependent mechanisms as evidenced by increased growth in hormone-free medium and estrogen medium, as well as reduced growth with ER knockdown by siRNA. Nuclear TBLR1 overexpression also increased migration and invasion in both breast and ovarian cancer cells. Determining the functional relationship between TBLR1 and ER may provide insights to develop novel treatment strategies and improve response to hormonal therapy in breast and ovarian cancers.
Department of Pathology, New York University School of Medicine New York, NY.
Xinyu
X
Wu
Structural & Cellular Biology, Tulane University School of Medicine New Orleans, LA.
Yang
Y
Zhan
Basic Science and Craniofacial Biology, New York University College of DentistryNew York, NY; Department of Urology, New York University School of MedicineNew York, NY; Department of NYU Cancer Institute, New York University School of MedicineNew York, NY.
Xin
X
Li
Department of Pathology, Northwestern School of Medicine Chicago, IL.
Jianjun
J
Wei
Department of Pathology, New York University School of Medicine New York, NY.
Larion
L
Santiago
Department of Pathology, New York University School of Medicine New York, NY.
Garrett
G
Daniels
Department of Pathology, New York University School of Medicine New York, NY.
Fangming
F
Deng
Department of Pathology, New York University School of Medicine New York, NY.
Xuelin
X
Zhong
Department of Pathology, New York University School of Medicine New York, NY.
Luis
L
Chiriboga
Department of Pathology, New York University School of Medicine New York, NY.
Ross
R
Basch
Department of Pathology, New York University School of Medicine New York, NY.
Sheng
S
Xiong
Structural & Cellular Biology, Tulane University School of Medicine New Orleans, LA.
Yan
Y
Dong
Department of Pathology, Hofstra North Shore-LIJ School of Medicine Hempstead, New York, NY.
Xinmin
X
Zhang
Department of Pathology, New York University School of MedicineNew York, NY; Department of Urology, New York University School of MedicineNew York, NY; Department of NYU Cancer Institute, New York University School of MedicineNew York, NY; Department of New York Harbor Healthcare System, New York University School of MedicineNew York, NY.
Peng
P
Lee
Breast cancer; TBL1XR1; estrogen receptor; nuclear TBLR1; ovarian cancer