CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer

Implication for a potential clinical relevance in trastuzumab treatment

Emanuela Brunetto, Anna Maria Ferrara, Francesca Rampoldi, Anna Talarico, Elena DalCin, Greta Grassini, Lorenzo Spagnuolo, Isabella Sassi, Antonella Ferro, Lucia Veronica Cuorvo, Mattia Barbareschi, Sara Piccinin, Roberta Maestro, Lorenza Pecciarini, Claudio Doglioni, Maria Giulia Cangi

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2) in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P =.007). Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P =.005). Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3-kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P =.018 for the metastatic cohort and P =.021 for the neoadjuvant cohort). Our findings highlight a link between HER2 and CDC25A that positively modulates HER2- targeted therapy response, suggesting that, in HER2-positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity.

Original languageEnglish
Pages (from-to)579-590
Number of pages12
JournalNeoplasia (United States)
Volume15
Issue number6
DOIs
Publication statusPublished - 2013

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Protein Stability
Breast Neoplasms
Therapeutics
human ERBB2 protein
Trastuzumab
Carcinogenesis
Breast
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
Penetrance
DNA Damage
Cell Survival
Cell Cycle
Down-Regulation
Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research

Cite this

CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer : Implication for a potential clinical relevance in trastuzumab treatment. / Brunetto, Emanuela; Maria Ferrara, Anna; Rampoldi, Francesca; Talarico, Anna; DalCin, Elena; Grassini, Greta; Spagnuolo, Lorenzo; Sassi, Isabella; Ferro, Antonella; Veronica Cuorvo, Lucia; Barbareschi, Mattia; Piccinin, Sara; Maestro, Roberta; Pecciarini, Lorenza; Doglioni, Claudio; Cangi, Maria Giulia.

In: Neoplasia (United States), Vol. 15, No. 6, 2013, p. 579-590.

Research output: Contribution to journalArticle

Brunetto, E, Maria Ferrara, A, Rampoldi, F, Talarico, A, DalCin, E, Grassini, G, Spagnuolo, L, Sassi, I, Ferro, A, Veronica Cuorvo, L, Barbareschi, M, Piccinin, S, Maestro, R, Pecciarini, L, Doglioni, C & Cangi, MG 2013, 'CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer: Implication for a potential clinical relevance in trastuzumab treatment', Neoplasia (United States), vol. 15, no. 6, pp. 579-590. https://doi.org/10.1593/neo.122054
Brunetto, Emanuela ; Maria Ferrara, Anna ; Rampoldi, Francesca ; Talarico, Anna ; DalCin, Elena ; Grassini, Greta ; Spagnuolo, Lorenzo ; Sassi, Isabella ; Ferro, Antonella ; Veronica Cuorvo, Lucia ; Barbareschi, Mattia ; Piccinin, Sara ; Maestro, Roberta ; Pecciarini, Lorenza ; Doglioni, Claudio ; Cangi, Maria Giulia. / CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer : Implication for a potential clinical relevance in trastuzumab treatment. In: Neoplasia (United States). 2013 ; Vol. 15, No. 6. pp. 579-590.
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AU - Maria Ferrara, Anna

AU - Rampoldi, Francesca

AU - Talarico, Anna

AU - DalCin, Elena

AU - Grassini, Greta

AU - Spagnuolo, Lorenzo

AU - Sassi, Isabella

AU - Ferro, Antonella

AU - Veronica Cuorvo, Lucia

AU - Barbareschi, Mattia

AU - Piccinin, Sara

AU - Maestro, Roberta

AU - Pecciarini, Lorenza

AU - Doglioni, Claudio

AU - Cangi, Maria Giulia

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