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Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling

Roswall, Pernilla; Bocci, Matteo LU ; Bartoschek, Michael LU ; Li, Hong; Kristiansen, Glen; Jansson, Sara LU ; Lehn, Sophie LU ; Sjölund, Jonas LU ; Reid, Steven LU and Larsson, Christer LU , et al. (2018) In Nature Medicine 24. p.463-473
Abstract

Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention of PDGF-CC activity in... (More)

Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention of PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that specification of breast cancer to the basal-like subtype is under microenvironmental control and is therapeutically actionable.

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Nature Medicine
volume
24
pages
463 - 473
publisher
Nature Publishing Group
external identifiers
  • scopus:85045313361
ISSN
1546-170X
DOI
10.1038/nm.4494
language
English
LU publication?
yes
id
db722ef0-ee34-4c0a-920b-a56604989987
date added to LUP
2018-03-21 14:31:37
date last changed
2019-03-12 04:07:06
@article{db722ef0-ee34-4c0a-920b-a56604989987,
  abstract     = {<p>Breast tumors of the basal-like, hormone receptor-negative subtype remain an unmet clinical challenge, as there is high rate of recurrence and poor survival in patients following treatment. Coevolution of the malignant mammary epithelium and its underlying stroma instigates cancer-associated fibroblasts (CAFs) to support most, if not all, hallmarks of cancer progression. Here we delineate a previously unappreciated role for CAFs as determinants of the molecular subtype of breast cancer. We identified paracrine crosstalk between cancer cells expressing platelet-derived growth factor (PDGF)-CC and CAFs expressing the cognate receptors in human basal-like mammary carcinomas. Genetic or pharmacological intervention of PDGF-CC activity in mouse models of cancer resulted in conversion of basal-like breast cancers into a hormone receptor-positive state that enhanced sensitivity to endocrine therapy in previously resistant tumors. We conclude that specification of breast cancer to the basal-like subtype is under microenvironmental control and is therapeutically actionable.</p>},
  author       = {Roswall, Pernilla and Bocci, Matteo and Bartoschek, Michael and Li, Hong and Kristiansen, Glen and Jansson, Sara and Lehn, Sophie and Sjölund, Jonas and Reid, Steven and Larsson, Christer and Eriksson, Pontus and Anderberg, Charlotte and Cortez, Eliane and Saal, Lao H and Orsmark-Pietras, Christina and Cordero, Eugenia and Haller, Bengt Kristian and Häkkinen, Jari and Burvenich, Ingrid J G and Lim, Elgene and Orimo, Akira and Höglund, Mattias and Rydén, Lisa and Moch, Holger and Scott, Andrew M and Eriksson, Ulf and Pietras, Kristian},
  issn         = {1546-170X},
  language     = {eng},
  month        = {03},
  pages        = {463--473},
  publisher    = {Nature Publishing Group},
  series       = {Nature Medicine},
  title        = {Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling},
  url          = {http://dx.doi.org/10.1038/nm.4494},
  volume       = {24},
  year         = {2018},
}