Pten in stromal fibroblasts suppresses mammary epithelial tumours.
The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.
Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA.
Anthony J
AJ
Trimboli
Carmen Z
CZ
Cantemir-Stone
Fu
F
Li
Julie A
JA
Wallace
Anand
A
Merchant
Nicholas
N
Creasap
John C
JC
Thompson
Enrico
E
Caserta
Hui
H
Wang
Jean-Leon
JL
Chong
Shan
S
Naidu
Guo
G
Wei
Sudarshana M
SM
Sharma
Julie A
JA
Stephens
Soledad A
SA
Fernandez
Metin N
MN
Gurcan
Michael B
MB
Weinstein
Sanford H
SH
Barsky
Lisa
L
Yee
Thomas J
TJ
Rosol
Paul C
PC
Stromberg
Michael L
ML
Robinson
Francois
F
Pepin
Michael
M
Hallett
Morag
M
Park
Michael C
MC
Ostrowski
Gustavo
G
Leone
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007113:Immunity, Innate; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050787:Proto-Oncogene Protein c-ets-2 / Q000172:deficiency / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*
C494070:Ets2 protein, mouse; D050787:Proto-Oncogene Protein c-ets-2; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse