Science and Technology Production
Congress
Authorship
Bruni, Sofia
;
De Martino, Mara
;
Proietti, Cecila Jazmín
;
Elizalde, Patricia V.
;
Schillaci, Roxana
;
MERCOGLIANO, MARIA FLORENCIA
Date
2016
Publishing House and Editing Place
ESTUDIO SIGMA S.R.L.
ISSN
1669-9106
Summary
Information provided by the agent in
SIGEVA
HER2 positive (HER2+) is a breast cancer (BC) subtype characterized by HER2 overexpression/amplification and affects ~15% of BC patients, who receive trastuzumab (T), an anti-HER2 monoclonal antibody, but resistance events hamper its clinical benefits in 40-60% of the cases. We have demonstrated that TNFα overexpression turned T-sensitive cells and tumors into resistant ones, and this resistance mechanism was mediated by upregulation of mucin 4 (MUC4). Nowadays there are new anti-HER2 the...
HER2 positive (HER2+) is a breast cancer (BC) subtype characterized by HER2 overexpression/amplification and affects ~15% of BC patients, who receive trastuzumab (T), an anti-HER2 monoclonal antibody, but resistance events hamper its clinical benefits in 40-60% of the cases. We have demonstrated that TNFα overexpression turned T-sensitive cells and tumors into resistant ones, and this resistance mechanism was mediated by upregulation of mucin 4 (MUC4). Nowadays there are new anti-HER2 therapies such as the dual tyrosine kinase inhibitor lapatinib (L) and antibodies, like T-DM1 and pertuzumab (P). The aim of this work was to explore whether TNF and TNF-induced MUC4 expression play a role as a multiresistance factor to these new therapies.We performed cell proliferation assays by cell count and by 3H-thymidine incorporation using T-sensitive (C) and T-resistant BT-474 cells (T2), the latter engineered to overexpress TNF. The combination of T+P (10 μg/ml each) was more effective that T alone in C cells (?65.7% and -30.6% respectively, and, P <0.001). T2 cells proliferation was slightly inhibited with T+P treatment (-24.1%, n.s).Dose-response curves showed that L inhibits C cells proliferation at 1 μM (-51.8%, P<0.0001 vs vehicle) and T-DM1 at 0.01 μg/ml (-40.7% vs IgG P<0.05), whereas T2 cells were resistant to both treatments at these concentrations. On the other hand, when MUC4 expression was abrogated, T2 cells were sensitized to T-DM1, showing that TNF-induced MUC4 expression is responsible for T-DM1 resistance in this cell line. These results suggest that overexpression of TNF in HER2+ BC confers resistance to T+P, T-DM1 and lapatinib. For T-DM1 treatment this resistance is mediated by TNF-induced MUC4 expression. We then propose to study MUC4 and TNF expression in tumor samples. Furthermore, resistant patients to HER2-targeted therapies with expression of TNF and MUC4, could be eligible for a combination with a TNF blocking treatment to overcome resistance.
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Key Words
BREAST CANCERTNF ALPHAHER2 POSITIVEMULTIRESISTANCE