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Oncogene. 2015 Jan 15;34(3):323-33. doi: 10.1038/onc.2013.553. Epub 2014 Jan 13.

Estrogen-dependent sushi domain containing 3 regulates cytoskeleton organization and migration in breast cancer cells.

Author information

1
Division of Reproductive Biology, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
2
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
3
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Abstract

Aromatase inhibitors (AIs) are the standard endocrine therapy for postmenopausal breast cancer; however, currently used biomarkers, such as, estrogen receptor-alpha/progesterone receptor (ERα/PR), predict only slightly more than half of the potential responders to AI treatment. To identify novel markers of AI responsiveness, a genome-wide microarray analysis was performed using primary breast tumor samples from 50 postmenopausal women who later developed metastatic breast cancer. Sushi domain containing 3 (SUSD3) is a significantly differentially expressed gene, with 3.38-fold higher mRNA levels in AI-responsive breast tumors vs non-responders (P<0.001). SUSD3 was highly expressed in ERα-positive breast tumors and treatment with estradiol increased SUSD3 expression in ERα-positive breast cancer cells. Treatment with an antiestrogen or ERα knockdown abolished basal and estradiol-dependent SUSD3 expression. Recruitment of ERα upstream of the transcription start site of SUSD3 was demonstrated by chromatin immunoprecipitation-PCR. Flow cytometric analysis of SUSD3-knockdown cells revealed blunted estradiol effects on progression into S and M phases. SUSD3 was localized to the plasma membrane of breast cancer cells. SUSD3 knockdown decreased the appearance of actin-rich protrusions, stress fibers and large basal focal adhesions, while increasing the presence of cortical actin concomitant with a decrease in Rho and focal adhesion kinase activity. SUSD3-deficient cells demonstrated diminished cell spreading, cell-cell adhesion and motility. In conclusion, SUSD3 is a novel promoter of estrogen-dependent cell proliferation and regulator of cell-cell and cell-substrate interactions and migration in breast cancer. It may serve as a novel predictor of response to endocrine therapy and potential therapeutic target.

PMID:
24413080
PMCID:
PMC4096609
DOI:
10.1038/onc.2013.553
[Indexed for MEDLINE]
Free PMC Article
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