p130Cas promotes invasiveness of three-dimensional ErbB2-transformed mammary acinar structures by enhanced activation of mTOR/p70S6K and Rac1

Tornillo, Giusy; Bisarò, Brigitte; Camacho-Leal, Maria del Pilar; Galiè, Mirco; Provero, Paolo; Stefano, Paola Di; Turco, Emilia; Defilippi, Paola; Cabodi, Sara

doi:10.1016/j.ejcb.2010.09.002

Cited by 29 publications

(46 citation statements)

References 58 publications

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“…Nevertheless, investigation of its expression in biopsies of different human malignancies using immunohistochemistry is still limited to breast cancer and haematological malignancies (Table I). Recently it has been reported that in human breast cancers overexpression of both ERBB2 and p130CAS is associated with increased proliferation, metastasis formation and poor prognosis 13,14 (Table I). Consistently, double transgenic mice overexpressing both p130CAS and ERBB2 in the mammary gland show an accelerated onset of tumour formation, providing evidence that p130CAS and the ERBB2 oncogene synergise in vivo to transform the mammary epithelium 13 (Table II).…”

Section: Integrin Adaptors In Cancermentioning

confidence: 99%

“…In ERBB2-transformed cells, p130CAS overexpression confers invasive properties in 3D cultures, sustaining and strengthening PI3K/AKT and ERK1/2/p70S6K signalling downstream of ERBB2, which led to RAC1 activation and MMP9 secretion 11 , respectively 14 . Consistently, p130CAS silencing in ERBB2-dependent breast carcinoma impairs migration and invasion in vitro as well as the formation of lung metastases in vivo 11 .…”

Section: Migration and Invasionmentioning

confidence: 99%

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Integrin signalling adaptors: not only figurants in the cancer story

et al. 2010

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Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor receptor activation. The understanding of the biological effects regulated by these adaptors in tumours might be crucial for the identification of novel targets and the development of innovative therapeutic strategies for human cancer. In this review we will discuss the relevance of adaptor proteins in signalling originating from integrin-mediated cell-extracellular matrix (ECM) adhesion and growth factor stimulation within the context of cell transformation and tumour progression.Herein, we will specifically underline the contribution of p130CAS, NEDD9, CRK, and the IPP complex (ILK, PINCH and PARVIN) to cancer, along with the more recently identified p140CAP.

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Section: Integrin Adaptors In Cancermentioning

confidence: 99%

Section: Migration and Invasionmentioning

confidence: 99%

Integrin signalling adaptors: not only figurants in the cancer story

et al. 2010

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“…Interestingly, concomitant p130Cas/ErbB2 overexpression accelerates the onset of mammary tumors, which are characterized at the molecular level by increased activation of c-Src and Akt [26]. Notably, a positive correlation between the expression of BCAR1/p130Cas and ErbB2 has been found in human breast cancers and the coexpression of these two genes is associated with shorter overall survival and a higher risk of developing distant metastasis [25,26] (Figure 2). …”

Section: Erbb2 Signaling Mediated By the Adaptor Proteins P130casmentioning

confidence: 99%

“…The administration of p130Cas stabilized siRNAs by intranipple injection in the mammary glands of mice with spontaneous ErbB2 cancer lesions, signiicantly impaired lesions growth, indicating that p130Cas might be a potential therapeutic target [24]. It has also been reported that p130Cas binds to ErbB2 and its overexpression is suicient to transactivate the ErbB2 receptor leading to the formation of a macromolecular signaling complex, in which Src and p125Fak kinases are present, that sustains ErbB2 downstream signaling pathways leading to activation of both MAPK and PI3K pathways regulating cell transformation, invasion and migration [24,25]. Interestingly, concomitant p130Cas/ErbB2 overexpression accelerates the onset of mammary tumors, which are characterized at the molecular level by increased activation of c-Src and Akt [26].…”

Section: Erbb2 Signaling Mediated By the Adaptor Proteins P130casmentioning

confidence: 99%

“…Indeed, the overexpression of p130Cas in ERbB2-transformed mammary acini leads to activation of PI3K/Akt and Erk1/2 MAPK signaling pathways and promote invasion of mammary acini. It was further demonstrated that Erk1/2 MAPK and PI3K/Akt-signaling triggers invasion through distinct downstream efectors involving mTOR/p70S6K and Rac1 activation [25]. The relevance of p130Cas in ErbB2-dependent invasion was further assessed by identifying the coding and noncoding genes that are diferentially expressed in p130Cas overexpressing and ErbB2 transformed invasive acini compared to ErbB2 transformed noninvasive multiacinar structures [42].…”

Section: Erbb2 Invasive Signaling Signaturementioning

confidence: 99%

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ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

Camacho-Leal¹,

Sciortino²,

Cabodi³

2017

Breast Cancer - From Biology to Medicine

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Overexpression of ErbB2 is found in several types of human carcinomas. In breast tumors, ErbB2 overexpression is detected in up to 20% of patients. Breast cancers in with ampliication of ErbB2 are characterized by rapid tumor growth, lower survival rate and increased disease progression. The molecular mechanisms underlying the oncogenic action of ErbB2 involve a complex signaling network that tightly regulates malignant cell migration and invasion and hence metastatic potential. Recent eforts have been made to identify gene expression signatures of ErbB2-positive invasive breast cancers that may represent important mediators of ErbB2-induced tumorigenesis and metastatic progression.In this chapter, we will discuss the canonical ErbB2 signaling pathways responsible for tumor growth and dissemination along with newly identiied mediators such as adaptor protein p130Cas and miRNAs. From a therapeutic point of view, the treatment with anti-ErbB2 monoclonal antibody trastuzumab has greatly improved the outcomes of patients with ErbB2 aggressive cancer. Nevertheless, de novo and acquired resistance to trastuzumab therapy still represent a major clinical problem. In the second part of the chapter, we will provide an overview of the mechanisms so far implicated in the onset of resistance to targeted therapy and of the new strategies to overcome resistance.

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p130Cas alters the differentiation potential of mammary luminal progenitors by deregulating c-Kit activity

Tornillo¹,

Elia²,

Castellano

et al. 2013

Stem Cells

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It has recently been proposed that defective differentiation of mammary luminal progenitors predisposes to basal-like breast cancer. However, the molecular and cellular mechanisms involved are still unclear. Here, we describe that the adaptor protein p130Cas is a crucial regulator of mouse mammary epithelial cell (MMEC) differentiation. Using a transgenic mouse model, we show that forced p130Cas overexpression in the luminal progenitor cell compartment results in the expansion of luminal cells, which aberrantly display basal cell features and reduced differentiation in response to lactogenic stimuli. Interestingly, MMECs overexpressing p130Cas exhibit hyperactivation of the tyrosine kinase receptor c-Kit. In addition, we demonstrate that the constitutive c-Kit activation alone mimics p130Cas overexpression, whereas c-Kit downregulation is sufficient to reestablish proper differentiation of p130Cas overexpressing cells. Overall, our data indicate that high levels of p130Cas, via abnormal c-Kit activation, promote mammary luminal cell plasticity, thus providing the conditions for the development of basal-like breast cancer. Consistently, p130Cas is overexpressed in human triple-negative breast cancer, further suggesting that p130Cas upregulation may be a priming event for the onset of basal-like breast cancer. STEM

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p130Cas promotes invasiveness of three-dimensional ErbB2-transformed mammary acinar structures by enhanced activation of mTOR/p70S6K and Rac1

Cited by 29 publications

References 58 publications

Integrin signalling adaptors: not only figurants in the cancer story

Integrin signalling adaptors: not only figurants in the cancer story

ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

p130Cas alters the differentiation potential of mammary luminal progenitors by deregulating c-Kit activity

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