Opposing roles of TGFβ and BMP signaling in prostate cancer development

Xin Lu; Eun-Jung Jin; Xi Cheng; Shan Feng; Xiaoying Shang; Pingna Deng; Shan Jiang; Qing Chang; Sharif Rahmy; Seema Chaudhary; Xuemin Lu; Ren Zhao; Y Alan Wang; Ronald A DePinho

doi:10.1101/gad.307116.117

Opposing roles of TGFβ and BMP signaling in prostate cancer development

Genes Dev. 2017 Dec 1;31(23-24):2337-2342. doi: 10.1101/gad.307116.117.

Authors

Xin Lu^{1

2

3}, Eun-Jung Jin^{1

4}, Xi Cheng^{2

5}, Shan Feng^{2

6}, Xiaoying Shang¹, Pingna Deng¹, Shan Jiang⁷, Qing Chang⁷, Sharif Rahmy², Seema Chaudhary², Xuemin Lu², Ren Zhao⁵, Y Alan Wang¹, Ronald A DePinho¹

Affiliations

¹ Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
² Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, Indiana 46556, USA.
³ Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana 46202, USA.
⁴ Department of Biological Science, Wonkwang University, Cheonbuk, Iksan 570-749, South Korea.
⁵ Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁶ School of Life Sciences, Tsinghua University, Beijing 100084, China.
⁷ Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.

Abstract

SMAD4 constrains progression of Pten-null prostate cancer and serves as a common downstream node of transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) pathways. Here, we dissected the roles of TGFβ receptor II (TGFBR2) and BMP receptor II (BMPR2) using a Pten-null prostate cancer model. These studies demonstrated that the molecular actions of TGFBR2 result in both SMAD4-dependent constraint of proliferation and SMAD4-independent activation of apoptosis. In contrast, BMPR2 deletion extended survival relative to Pten deletion alone, establishing its promoting role in BMP6-driven prostate cancer progression. These analyses reveal the complexity of TGFβ-BMP signaling and illuminate potential therapeutic targets for prostate cancer.

Keywords: BMPR2; PTEN; SMAD4; TGFBR2; bone metastasis; prostate cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Bone Morphogenetic Protein Receptors, Type II / genetics*
Bone Morphogenetic Protein Receptors, Type II / metabolism*
Bone Neoplasms / genetics
Bone Neoplasms / secondary
Disease Models, Animal
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genotype
Kaplan-Meier Estimate
Male
Mice
Mice, Inbred C57BL
PTEN Phosphohydrolase / genetics
Prostatic Neoplasms / genetics
Prostatic Neoplasms / physiopathology*
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism*
Receptor, Transforming Growth Factor-beta Type II
Receptors, Transforming Growth Factor beta / genetics*
Receptors, Transforming Growth Factor beta / metabolism*
Signal Transduction*
Smad4 Protein / genetics
Smad4 Protein / metabolism

Substances

Receptors, Transforming Growth Factor beta
Smad4 Protein
Protein Serine-Threonine Kinases
Bone Morphogenetic Protein Receptors, Type II
Receptor, Transforming Growth Factor-beta Type II
PTEN Phosphohydrolase

Abstract

Publication types

MeSH terms

Substances

Grants and funding