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

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.

• Authors: Cristiana Ercolani, Anna Di Benedetto, Irene Terrenato, Laura Pizzuti, Luigi Di Lauro, Domenico Sergi, Francesca Sperati, Simonetta Buglioni, Maria Teresa Ramieri, Lucia Mentuccia, Teresa Gamucci, Letizia Perracchio, Edoardo Pescarmona, Marcella Mottolese, Maddalena Barba, Patrizia Vici, Ruggero De Maria, Marcello Maugeri-Saccà
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 18 Issue 5 Pg. 339-346 (05 04 2017) ISSN: 1555-8576 [Electronic] United States
• PMID: 28387539 (Publication Type: Journal Article)

Chemical References

• Proto-Oncogene Proteins
• macrophage stimulating protein
• Hepatocyte Growth Factor
• LATS1 protein, human
• ERBB2 protein, human
• Receptor, ErbB-2
• Protein Serine-Threonine Kinases

Topics

• Adult
• Aged
• Cell Proliferation (drug effects)
• DNA Damage (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Hepatocyte Growth Factor (genetics)
• Humans
• Lymphocytes, Tumor-Infiltrating (drug effects, pathology)
• Middle Aged
• Neoadjuvant Therapy
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (genetics)
• Proto-Oncogene Proteins (genetics)
• Receptor, ErbB-2 (genetics)
• Signal Transduction (drug effects)
• Triple Negative Breast Neoplasms (drug therapy, genetics, pathology)