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Tesi etd-03262018-115828

Thesis type
Tesi di dottorato di ricerca
Investigation on the molecular mechanisms underlying response to neoadjuvant therapy with Trastuzumab in HER-2 positive human breast cancer patients: ANKRD44 gene, as a new molecular factor involved in drug resistance
Settore scientifico disciplinare
Corso di studi
tutor Dott.ssa Mazzanti, Chiara Maria
relatore Prof. Naccarato, Antonio Giuseppe
Parole chiave
  • ANKRD44
  • Trastuzumab resistance
  • HER2+ breast cancer
  • Next generation sequencing
  • gene silencing
Data inizio appello
Data di rilascio
Riassunto analitico
HER-2 receptor is overexpressed in 20-30 % of breast cancer (BC) and it has been chosen to be an effective therapeutic target of Trastuzumab, a humanized monoclonal antibody, approved by FDA. The mechanism by which this drug exerts its antitumor activity is not fully understood. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. An understanding of Trastuzumab resistance mechanisms would be a helpful tool in the development of rational drug combinations to circumvent resistance and allow better selection of patients likely to respond. Through whole-exome sequencing on 12 primary FFPE biopsies of HER2+/hormone receptor negative (ER-/PgR-) BC patients specifically selected for different response to the neoadjuvant therapy with Trastuzumab, we identify 18 informative gene mutations which selectively discriminate patients according to their response to the therapy. Among these genes, we identified ANKRD44 gene as a possible cofactor in establishing Trastuzumab resistance. By silencing ANKRD44 gene in HER-2+ breast cancer cells (BT474) we obtained a Trastuzumab-partially resistant human breast cancer cell line (shANK) in which NF-kβ is constitutively activated through the TAK1/Akt pathway. The activation of this pathway promotes also an increased glycolysis rate in resistant cells confirmed by the up-regulation of LDHB protein and an increase in TROP2 protein expression which is well known to be associated with more aggressive cancer phenotypes. Together these results identify ANKRD44 gene as a cofactor for Trastuzumab resistance but also as a possible predictive marker for the response to the neoadjuvant therapy with Trastuzumab. Moreover, it supports NF-kβ inhibition as a strategy for improving cell sensitivity to Trastuzumab.