TY - JOUR
T1 - Receptor tyrosine kinase signaling favors a protumorigenic state in breast cancer cells by inhibiting the adaptive immune response
AU - Ursini-Siegel, Josie
AU - Cory, Sean
AU - Zuo, Dongmei
AU - Hardy, William R.
AU - Rexhepaj, Elton
AU - Lam, Sonya
AU - Schade, Babette
AU - Jirstrom, Karin
AU - Bjur, Eva
AU - Piccirillo, Ciriaco A.
AU - DeNardo, David
AU - Coussens, Lisa M.
AU - Brennan, Donal J.
AU - Gallagher, William M.
AU - Park, Morag
AU - Pawson, Tony
AU - Hallett, Michael
AU - Muller, William J.
PY - 2010/10/15
Y1 - 2010/10/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78049271279&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-2229
DO - 10.1158/0008-5472.CAN-10-2229
M3 - Article
C2 - 20924104
AN - SCOPUS:78049271279
SN - 0008-5472
VL - 70
SP - 7776
EP - 7787
JO - Cancer research
JF - Cancer research
IS - 20
ER -