News archives


OCTOBER - DECEMBER 17

JULY - SEPTEMBER 17

APRIL - JUNE 17

JANUARY - MARCH 17

OCTOBER - DECEMBER 16

JULY - SEPTEMBER 16

APRIL - JUNE 16

JANUARY - MARCH 16

OCTOBER - DECEMBER 15

JULY - SEPTEMBER 15

APRIL - JUNE 15

JANUARY - MARCH 15

OCTOBER - DECEMBER 14

JULY - SEPTEMBER 14

APRIL - JUNE 14

JANUARY - MARCH 14

OCTOBER - DECEMBER 13

JULY - SEPTEMBER 13

APRIL - JUNE 13

JANUARY - MARCH 13

OCTOBER - DECEMBER 12

JULY - SEPTEMBER 12

APRIL - JUNE 12

JANUARY - MARCH 12

OCTOBER - DECEMBER 11

JULY - SEPTEMBER 11

APRIL - JUNE 11

JANUARY - MARCH 11

OCTOBER - DECEMBER 10

JULY - SEPTEMBER 10

APRIL - JUNE 10

JANUARY - MARCH 10

OCTOBER - DECEMBER 09

JULY - SEPTEMBER 09

APRIL - JUNE 09

JANUARY - MARCH 09

OCTOBER - DECEMBER 08

JULY - SEPTEMBER 08

APRIL - JUNE 08

JANUARY - MARCH 08

OCTOBER - DECEMBER 07

JULY - SEPTEMBER 07

APRIL - JUNE 07

JANUARY - MARCH 07

 
  current news   Press   selected story    
     
  18 November 2016  
 
Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression
 
 




Authors
Roberto Rangela, Song-Choon Leeb, Kenneth Hon-Kim Banb,c, Liliana Guzman-Rojasa, Michael B. Manna, Justin Y. Newberga, Takahiro Kodamaa, Leslie A. McNoed, Luxmanan Selvanesand, Jerrold M. Wardb,1, Alistair G. Ruste,2, Kuan-Yew Chinb, Michael A. Blackd, Nancy A. Jenkinsa.b.3, and Neal G. Copelanda.b.3.4

a  Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030
b  Division of Genomics and Genetics, Institute of Molecular and Cell Biology, Agency for Science,    Technology and Research, Biopolis, Singapore 138673
c  Deparment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,    Singapore 138673
d  Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
e  Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH,
   United Kingdom

Published online in PNAS before print on November 14, 2016.

Abstract
Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1. Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.



Figure Legend:
SB mutagenesis promotes the development of multiple mammary tumor subtypes. (A) Kaplan–Meier survival curves of five different genotypic combinations of mice. Pten/SB–Onc2 and Pten/SB–Onc3 mice showed significant tumor acceleration compared with various control mice (Pten/SB–Onc2, P = 0.0003; Pten/SB–Onc3, P = 0.0001). (B and C) H&E or immunohistochemical staining of mammary adenocarcinoma (B) or adenosquamous carcinoma (C). The adenocarcinoma shows areas of less differentiation (Upper H&E). The adenosquamous carcinoma also has areas of no squamous differentiation invading muscle (Lower H&E). Both tumors showed a high degree of heterogeneity, expressing both basal (CK14) and luminal (CK18) cytokeratins. Both tumors have low or focal high-proliferation rate tumors, based upon their Ki67 staining (NOTE-B shows a focally high rate), and express high levels of nuclear SBT protein. (Scale bar, 100 μm.) (D) Mammary tumor subtype classification based upon its PAM50 expression signature (31). The heat map displays gene expression data (log scale, right legend) for the PAM50 breast cancer subtype classifier for each mouse tumor (columns). The left side indicates the centroids for each breast cancer subtype. The rows in the heat map represent genes in the PAM50 panel, and columns represent each mammary tumor. Top panels show proliferation scores (blue, low; red, high) and PAM50 subtypes: basal-like (black), Her2 (purple), luminal A (light blue), and normal-like (light green).