RKIP and HMGA2 regulate breast tumor survival and metastasis through lysyl oxidase and syndecan-2

TY - JOUR

T1 - RKIP and HMGA2 regulate breast tumor survival and metastasis through lysyl oxidase and syndecan-2

AU - Sun, M.

AU - Gomes, S.

AU - Chen, P.

AU - Frankenberger, C. A.

AU - Sankarasharma, D.

AU - Chung, C. H.

AU - Chada, K. K.

AU - Rosner, M. R.

N1 - Funding Information: This work was supported by NIH grant GM087630 to MRR and DOD Predoctoral Traineeship Award W81XWH-10-1-0396 to MS. We also thank Eva Eves for technical support and helpful discussion.

PY - 2014/7/3

Y1 - 2014/7/3

N2 - Elucidating targets of physiological tumor metastasis suppressors can highlight key signaling pathways leading to invasion and metastasis. To identify downstream targets of the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP/PEBP1), we utilized an integrated approach based upon statistical analysis of tumor gene expression data combined with experimental validation. Previous studies from our laboratory identified the architectural transcription factor and oncogene, high mobility group AT-hook 2 (HMGA2), as a target of inhibition by RKIP. Here we identify two signaling pathways that promote HMGA2-driven metastasis. Using both human breast tumor cells and an MMTV-Wnt mouse breast tumor model, we show that RKIP induces and HMGA2 inhibits expression of miR-200b; miR-200b directly inhibits expression of lysyl oxidase (LOX), leading to decreased invasion. RKIP also inhibits syndecan-2 (SDC2), which is aberrantly expressed in breast cancer, via downregulation of HMGA2; but this mechanism is independent of miR-200. Depletion of SDC2 induces apoptosis and suppresses breast tumor growth and metastasis in mouse xenografts. RKIP, LOX and SDC2 are coordinately regulated and collectively encompass a prognostic signature for metastasis-free survival in ER-negative breast cancer patients. Taken together, our findings reveal two novel signaling pathways targeted by the metastasis suppressor RKIP that regulate remodeling of the extracellular matrix and tumor survival.

AB - Elucidating targets of physiological tumor metastasis suppressors can highlight key signaling pathways leading to invasion and metastasis. To identify downstream targets of the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP/PEBP1), we utilized an integrated approach based upon statistical analysis of tumor gene expression data combined with experimental validation. Previous studies from our laboratory identified the architectural transcription factor and oncogene, high mobility group AT-hook 2 (HMGA2), as a target of inhibition by RKIP. Here we identify two signaling pathways that promote HMGA2-driven metastasis. Using both human breast tumor cells and an MMTV-Wnt mouse breast tumor model, we show that RKIP induces and HMGA2 inhibits expression of miR-200b; miR-200b directly inhibits expression of lysyl oxidase (LOX), leading to decreased invasion. RKIP also inhibits syndecan-2 (SDC2), which is aberrantly expressed in breast cancer, via downregulation of HMGA2; but this mechanism is independent of miR-200. Depletion of SDC2 induces apoptosis and suppresses breast tumor growth and metastasis in mouse xenografts. RKIP, LOX and SDC2 are coordinately regulated and collectively encompass a prognostic signature for metastasis-free survival in ER-negative breast cancer patients. Taken together, our findings reveal two novel signaling pathways targeted by the metastasis suppressor RKIP that regulate remodeling of the extracellular matrix and tumor survival.

KW - HMGA2

KW - LOX

KW - RKIP

KW - SDC2

KW - breast

KW - metastasis

UR - http://www.scopus.com/inward/record.url?scp=84903901117&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84903901117&partnerID=8YFLogxK

U2 - https://doi.org/10.1038/onc.2013.328

DO - https://doi.org/10.1038/onc.2013.328

M3 - Article

C2 - 23975428

SN - 0950-9232

VL - 33

SP - 3528

EP - 3537

JO - Oncogene

JF - Oncogene

IS - 27

ER -