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Observational Study
. 2019 Sep;99(9):1296-1308.
doi: 10.1038/s41374-019-0258-1. Epub 2019 Apr 25.

Repression of miR-135b-5p promotes metastasis of early-stage breast cancer by regulating downstream target SDCBP

Tianjie Pu  1   2 , Mengjia Shen  1   2 , Shi Li  3 , Libo Yang  1   2 , Hongwei Gao  2 , Lin Xiao  2 , Xiaorong Zhong  4   5 , Hong Zheng  4   5 , Yueping Liu  3 , Feng Ye  6   7   8 , Hong Bu  1   2   5   9
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Free article
Observational Study

Repression of miR-135b-5p promotes metastasis of early-stage breast cancer by regulating downstream target SDCBP

Tianjie Pu et al. Lab Invest. 2019 Sep.
Free article

Abstract

Metastasis is an essential event for breast cancer (BC) progression even after initial surgery. The identification of patients with a high probability of metastasis at an early stage is particularly important in clinical practice and requires individualized treatment or early prevention. A retrospective study of 242 cases of ductal carcinoma in situ with microinvasion (DCIS-Mi), the first stage of invasive BC, was performed in this follow-up analysis. Of all patients, 8 developed metastases, and they were all included for further mechanistic studies with control group of 24 DCIS-Mi by matched-pair designing. By screening DCIS-Mi with different prognoses, we found that the DCIS-Mi that metastasized had significantly lower miR-135b-5p expression than the DCIS-Mi that did not. The function of miR-135b-5p was studied in vitro and in vivo invasion and metastasis assays. We also validated a novel target gene for miR-135b-5p, syndecan binding protein (SDCBP), and assessed the functional consequences of SDCBP by invasion assays. By checking different BC cell lines, a strong inverse correlation between miR-135b-5p and SDCBP expression was recorded. For the functional study, the inhibition of miR-135b-5p was accompanied by increased BC cell growth, epithelial-mesenchymal transition (EMT), migration and invasion in vitro. Interestingly, silencing SDCBP can reverse miR-135b-5p-dependent EMT and proliferation. In vivo studies demonstrated that the newly revealed miR-135b-5p/SDCBP axis increased cell proliferation, invasion and malignant transformation, as well as promoted metastasis in a xenograft tumor mouse model. Thus, our clinical patient cohort and functional data suggest that miR-135b-5p/SDCBP is a crucial determinant of BC metastasis at a very early stage. Our results may shed light on the importance of miR-135b-5p molecular diagnosis and prognosis, as well as the early prevention of BC for metastasis.

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