Sara Cabodi
e-mail: sara.cabodi AT unito.it
affiliation: Università di Torino
research area(s): Cancer Biology
Course:
Biomedical Sciences and Human Oncology
University/Istitution: Università di Torino
University/Istitution: Università di Torino
Breast cancer is an aggressive malignancy affecting a large woman population, Even though important progress has been made in providing new therapies to treat this neoplasia, our knowledge on the mechanisms underlying the transformation of breast epithelial cells in tumor cells is still superficial. The neoplastic phenotype results from the alteration of multiple cellular signalling mechanisms controlling proliferation, survival and invasiveness. These signalling pathways arise from different classes of receptors, but often converge on common molecules giving raise to highly regulated and interconnected networks. A common point of convergence of different signalling pathways is the adaptor protein p130Cas (Crk associated substrate), which is involved both in integrin and growth factor receptor signalling. This protein, originally identified as the major substrate of the v-Src and v-Crk oncogenes, can bind to several signalling and adaptors molecules leading to the assembly of a molecular machinery controlling survival, motility and invasion. p130Cas is emerging as an important player in the transformation and invasion driven by different oncogenes. Antisense p130Cas constructs partially reversed cell transformation induced by ornithine decarboxylase, Ha-Ras and v-Src. p130Cas interacts with the anaplastic lymphoma kinase (ALK) in Anaplastic Large Cell Lymphomas (ALCL) and stromal tumours, regulating its transforming activities .
We have recently demonstrated in a transgenic mice model that p130Cas is involved in the development and differentiation of mammary gland. These mice are characterized by extensive mammary epithelial hyperplasia during development and pregnancy and by delayed involution at the end of lactation, associated with activation of signalling pathways, increased rate of proliferation and decreased apoptosis. A double-transgenic line derived from crossing MMTVp130Cas with MMTV-ErbB2 mice expressing the activated form of the rat ErbB2 oncogene develops multifocal mammary tumors with a significantly shorter latency than the ErbB2 parental strain alone. Consistently with the double-transgenic mice model, we found that p130Cas is overexpressed in a significant subset of human breast cancers and high levels of p130Cas in association with ErbB2 expression correlate with elevated proliferation. These findings provide evidences for a role of p130Cas as a positive regulator of both proliferation and survival in normal and transformed mammary epithelial cells thus indicating p130Cas as a potential therapeutic target.
Recently, alterations occurring in mammary stem cells have been proposed to be the source of many types of breast cancer. Mammary gland stem cells are a quiescent and self-renewing population within the mammary gland that are capable of giving rise to the differentiated ductal, alveolar and myoepithelial cells. Thus, the isolation and characterization of mammary stem cells is fundamental to understand mammary gland development and tissue homeostasis as well as breast oncogenesis.
Our current research activities are focused on three main projects:
(i) defining the role of p130Cas in ErbB2-dependent tumorigenesis.
(ii) characterization of the role of p130Cas in normal and cancer stem cells
(iii) defining the effect of p130Cas in estrogen-dependent development of the mammary gland
We have recently demonstrated in a transgenic mice model that p130Cas is involved in the development and differentiation of mammary gland. These mice are characterized by extensive mammary epithelial hyperplasia during development and pregnancy and by delayed involution at the end of lactation, associated with activation of signalling pathways, increased rate of proliferation and decreased apoptosis. A double-transgenic line derived from crossing MMTVp130Cas with MMTV-ErbB2 mice expressing the activated form of the rat ErbB2 oncogene develops multifocal mammary tumors with a significantly shorter latency than the ErbB2 parental strain alone. Consistently with the double-transgenic mice model, we found that p130Cas is overexpressed in a significant subset of human breast cancers and high levels of p130Cas in association with ErbB2 expression correlate with elevated proliferation. These findings provide evidences for a role of p130Cas as a positive regulator of both proliferation and survival in normal and transformed mammary epithelial cells thus indicating p130Cas as a potential therapeutic target.
Recently, alterations occurring in mammary stem cells have been proposed to be the source of many types of breast cancer. Mammary gland stem cells are a quiescent and self-renewing population within the mammary gland that are capable of giving rise to the differentiated ductal, alveolar and myoepithelial cells. Thus, the isolation and characterization of mammary stem cells is fundamental to understand mammary gland development and tissue homeostasis as well as breast oncogenesis.
Our current research activities are focused on three main projects:
(i) defining the role of p130Cas in ErbB2-dependent tumorigenesis.
(ii) characterization of the role of p130Cas in normal and cancer stem cells
(iii) defining the effect of p130Cas in estrogen-dependent development of the mammary gland
1) Cabodi S., Tinnirello A., Di Stefano P., Ambrosin E., Castellano I., Sapino A., Arisio R., Cavallo F., Forni G., Silengo L., Altruda F., Turco E., Tarone G., AND Defilippi P. p130Cas as a new regulator of mammary epithelial cell proliferation, survival and HER2-Neu oncogene dependent breast tumorigenesis. Cancer Research, 2006, May 1st.
2) Defilippi P, Di Stefano P, Cabodi S. p130Cas: a versatile scaffold in signaling networks.Trends Cell Biol. 2006 Mar 30.
3) Cabodi S, Morello V, Masi A, Cicchi R, Broggio C, Distefano P, Brunelli E, Silengo L, Pavone F, Arcangeli A, Turco E, Tarone G, Moro L, Defilippi P. Convergence of integrins and EGF receptor signalling via PI3K/Akt/FoxO pathway in early gene Egr-1 expression. J Cell Physiol. 2009 Feb;218(2):294-303.
4) Di Stefano P, Damiano L, Cabodi S, Aramu S, Tordella L, Praduroux A, Piva R, Cavallo F, Forni G, Silengo L, Tarone G, Turco E, Defilippi P. p140Cap protein suppresses tumour cell properties, regulating Csk and Src kinase activity. EMBO J. 2007 Jun 20;26(12):2843-55.
5) Cabodi S, Moro L, Bergatto E, Boeri Erba E, Di Stefano P, Turco E, Tarone G,Defilippi P. Integrin regulation of epidermal growth factor (EGF) receptor and of EGF-dependent responses. Biochem Soc Trans. 2004 Jun;32(Pt3):438-42. Review.
6) Cabodi S, Moro L, Baj G, Smeriglio M, Di Stefano P, Gippone S, Surico N, Silengo L, Turco E, Tarone G, Defilippi P. p130Cas interacts with estrogen receptor alpha and modulates non-genomic estrogen signaling in breast cancer cells. J Cell Sci. 2004 Mar 15;117(Pt 8):1603-11.
7) Cabodi S*, Di Stefano P, , Boeri Erba E, Margaria V, Bergatto E, Giuffrida MG, Silengo L, Tarone G, Turco E, Defilippi P. P130Cas-associated protein (p140Cap) as a new tyrosine-phosphorylated protein involved in cell spreading. Mol Biol Cell. 2004 Feb;15(2):787-800. *equally contributed authors
8) Moro L, Dolce L, Cabodi S, Bergatto E, Erba EB, Smeriglio M, Turco E, Retta SF, Giuffrida MG, Venturino M, Godovac-Zimmermann J, Conti A, Schaefer E, Beguinot L, Tacchetti C, Gaggini P, Silengo L, Tarone G, Defilippi P. “Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor
tyrosines”. J Biol Chem. 2002 Mar 15;277(11):9405-14.
9) Cabodi S, Calautti E, Talora C, Kuroki T, Stein PL, Dotto GP. “A PKC-eta/Fyn-dependent pathway leading to keratinocyte growth arrest and differentiation” Mol Cell. 2000 Nov;6(5):1121-9.
10) Calautti E, Cabodi S, Stein PL, Hatzfeld M, Kedersha N, Paolo Dotto G. “Tyrosine phosphorylation and src family kinases control keratinocyte cell-cell adhesion.” J Cell Biol. 1998 Jun 15;141(6):1449-65.
2) Defilippi P, Di Stefano P, Cabodi S. p130Cas: a versatile scaffold in signaling networks.Trends Cell Biol. 2006 Mar 30.
3) Cabodi S, Morello V, Masi A, Cicchi R, Broggio C, Distefano P, Brunelli E, Silengo L, Pavone F, Arcangeli A, Turco E, Tarone G, Moro L, Defilippi P. Convergence of integrins and EGF receptor signalling via PI3K/Akt/FoxO pathway in early gene Egr-1 expression. J Cell Physiol. 2009 Feb;218(2):294-303.
4) Di Stefano P, Damiano L, Cabodi S, Aramu S, Tordella L, Praduroux A, Piva R, Cavallo F, Forni G, Silengo L, Tarone G, Turco E, Defilippi P. p140Cap protein suppresses tumour cell properties, regulating Csk and Src kinase activity. EMBO J. 2007 Jun 20;26(12):2843-55.
5) Cabodi S, Moro L, Bergatto E, Boeri Erba E, Di Stefano P, Turco E, Tarone G,Defilippi P. Integrin regulation of epidermal growth factor (EGF) receptor and of EGF-dependent responses. Biochem Soc Trans. 2004 Jun;32(Pt3):438-42. Review.
6) Cabodi S, Moro L, Baj G, Smeriglio M, Di Stefano P, Gippone S, Surico N, Silengo L, Turco E, Tarone G, Defilippi P. p130Cas interacts with estrogen receptor alpha and modulates non-genomic estrogen signaling in breast cancer cells. J Cell Sci. 2004 Mar 15;117(Pt 8):1603-11.
7) Cabodi S*, Di Stefano P, , Boeri Erba E, Margaria V, Bergatto E, Giuffrida MG, Silengo L, Tarone G, Turco E, Defilippi P. P130Cas-associated protein (p140Cap) as a new tyrosine-phosphorylated protein involved in cell spreading. Mol Biol Cell. 2004 Feb;15(2):787-800. *equally contributed authors
8) Moro L, Dolce L, Cabodi S, Bergatto E, Erba EB, Smeriglio M, Turco E, Retta SF, Giuffrida MG, Venturino M, Godovac-Zimmermann J, Conti A, Schaefer E, Beguinot L, Tacchetti C, Gaggini P, Silengo L, Tarone G, Defilippi P. “Integrin-induced epidermal growth factor (EGF) receptor activation requires c-Src and p130Cas and leads to phosphorylation of specific EGF receptor
tyrosines”. J Biol Chem. 2002 Mar 15;277(11):9405-14.
9) Cabodi S, Calautti E, Talora C, Kuroki T, Stein PL, Dotto GP. “A PKC-eta/Fyn-dependent pathway leading to keratinocyte growth arrest and differentiation” Mol Cell. 2000 Nov;6(5):1121-9.
10) Calautti E, Cabodi S, Stein PL, Hatzfeld M, Kedersha N, Paolo Dotto G. “Tyrosine phosphorylation and src family kinases control keratinocyte cell-cell adhesion.” J Cell Biol. 1998 Jun 15;141(6):1449-65.
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