Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

C. Ercolani, A. Di Benedetto, I. Terrenato, L. Pizzuti, L. Di Lauro, D. Sergi, F. Sperati, S. Buglioni, M. T. Ramieri, L. Mentuccia, T. Gamucci, L. Perracchio, E. Pescarmona, M. Mottolese, M. Barba, P. Vici, R. De Maria, M. Maugeri-Sacca

Research output: Contribution to journalArticle

Abstract

The Hippo kinases MST1/2 and LATS1/2 inhibit the oncoproteins TAZ/YAP and regulate T cell function. Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). We hypothesized that MST1/2 and LATS1/2 localization differently impacts the efficacy of neoadjuvant therapy (NAT) in breast cancer, being protective when expressed in the cytoplasm of tumor cells and in tumor-infiltrating lymphocytes, whereas representing molecular determinants of chemoresistance when present in the nucleus as a consequence of their cooperation with the DDR. Diagnostic biopsies from 57 HER2-positive and triple-negative breast cancer patients treated with NAT were immunostained for evaluating the expression of phosphorylated MST1/2 (pMST1/2) and LATS1/2 (pLATS1/2) in tumor-infiltrating lymphocytes (TILs) and in cancer cells. TAZ and Chk1 immunostaining was exploited for investigating subcellular compartment-dependent activity of Hippo kinases. Nuclear pMST1/2 (pMST1/2nuc) expression was significantly associated with nuclear expression of Chk1 (p = 0.046), whereas cytoplasmic pMST1/2 (pMST1/2cyt) expression was marginally associated with cytoplasmic TAZ staining (p = 0.053). Patients whose tumors expressed pMST1/2nuc were at increased risk of residual disease after NAT (pCR ypT0/is ypN0: OR 4.91, 95%CI: 1.57-15.30; pCR ypT0 ypN0: OR 3.59, 95%CI 1.14-11.34). Conversely, exclusive cytoplasmic localization of pMST1/2 (pMST1/2cyt)seemed to be a protective factor (pCR ypT0/is ypN0: OR 0.34, 95%CI: 0.11-1.00; pCR ypT0 ypN0: OR 0.31, 95%CI 0.10-0.93). The subcellular localization-dependent significance of pMST1/2 expression suggests their involvement in different molecular networks with opposite impact on NAT efficacy. Larger studies are warranted to confirm these novel findings.
Original languageEnglish
Pages (from-to)339-346
Number of pages8
JournalCancer Biology and Therapy
Volume18
Issue number5
DOIs
Publication statusPublished - May 4 2017

Keywords

  • HER2-positive breast cancer
  • Hippo pathway
  • LATS 1/2
  • MST1/2
  • triple-negative breast cancer

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