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Receptor Tyrosine Kinase Signaling Favors a Protumorigenic State in Breast Cancer Cells by Inhibiting the Adaptive Immune Response

Ursini-Siegel, Josie; Cory, Sean; Zuo, Dongmei; Hardy, William R.; Rexhepaj, Elton; Lam, Sonya; Schade, Babette; Jirström, Karin LU ; Bjur, Eva and Piccirillo, Ciriaco A., et al. (2010) In Cancer Research 70(20). p.7776-7787
Abstract
Using transgenic mouse models of breast cancer that ablate Src homology and collagen A ( ShcA) expression or oncogene-coupled ShcA signaling, we previously showed that this adaptor is critical for mammary tumor onset and progression. We now provide the first evidence that ShcA regulates mammary tumorigenesis, in part, through its ability to regulate the adaptive immune response. Inactivation of ShcA signaling within tumor cells results in extensive CD4(+) T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA-deficient hyperplasias is accelerated in a T... (More)
Using transgenic mouse models of breast cancer that ablate Src homology and collagen A ( ShcA) expression or oncogene-coupled ShcA signaling, we previously showed that this adaptor is critical for mammary tumor onset and progression. We now provide the first evidence that ShcA regulates mammary tumorigenesis, in part, through its ability to regulate the adaptive immune response. Inactivation of ShcA signaling within tumor cells results in extensive CD4(+) T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA-deficient hyperplasias is accelerated in a T cell-deficient background. We also uncover a clinically relevant correlation between high ShcA expression and low CTL infiltration in human breast cancers. Finally, we define a novel ShcA-regulated immune signature that functions as an independent prognostic marker of survival in human epidermal growth factor receptor 2(+) and basal breast cancers. We reveal a novel role for tumor cell-derived ShcA in the establishment and maintenance of an immunosuppressive state. Cancer Res; 70(20); 7776-87. (C) 2010 AACR. (Less)
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Cancer Research
volume
70
issue
20
pages
7776 - 7787
publisher
American Association for Cancer Research Inc.
external identifiers
  • wos:000282879900006
  • scopus:78049271279
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-10-2229
language
English
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yes
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6904cda6-caa3-4f2f-9796-aa9ee98620a4 (old id 1726159)
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2010-12-03 12:09:35
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@article{6904cda6-caa3-4f2f-9796-aa9ee98620a4,
  abstract     = {Using transgenic mouse models of breast cancer that ablate Src homology and collagen A ( ShcA) expression or oncogene-coupled ShcA signaling, we previously showed that this adaptor is critical for mammary tumor onset and progression. We now provide the first evidence that ShcA regulates mammary tumorigenesis, in part, through its ability to regulate the adaptive immune response. Inactivation of ShcA signaling within tumor cells results in extensive CD4(+) T-cell infiltration and induction of a humoral immune response in mammary tumors. This is associated with a robust CTL response in preneoplastic lesions that are deficient in ShcA signaling. Moreover, mammary tumor progression of ShcA-deficient hyperplasias is accelerated in a T cell-deficient background. We also uncover a clinically relevant correlation between high ShcA expression and low CTL infiltration in human breast cancers. Finally, we define a novel ShcA-regulated immune signature that functions as an independent prognostic marker of survival in human epidermal growth factor receptor 2(+) and basal breast cancers. We reveal a novel role for tumor cell-derived ShcA in the establishment and maintenance of an immunosuppressive state. Cancer Res; 70(20); 7776-87. (C) 2010 AACR.},
  author       = {Ursini-Siegel, Josie and Cory, Sean and Zuo, Dongmei and Hardy, William R. and Rexhepaj, Elton and Lam, Sonya and Schade, Babette and Jirström, Karin and Bjur, Eva and Piccirillo, Ciriaco A. and DeNardo, David and Coussens, Lisa M. and Brennan, Donal J. and Gallagher, William M. and Park, Morag and Pawson, Tony and Hallett, Michael and Muller, William J.},
  issn         = {1538-7445},
  language     = {eng},
  number       = {20},
  pages        = {7776--7787},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Receptor Tyrosine Kinase Signaling Favors a Protumorigenic State in Breast Cancer Cells by Inhibiting the Adaptive Immune Response},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-10-2229},
  volume       = {70},
  year         = {2010},
}