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 (pMST1/2 nuc ) expression was significantly associated with nuclear expression of Chk1 (p D 0.046), whereas cytoplasmic pMST1/2 (pMST1/2 cyt ) expression was marginally associated with cytoplasmic TAZ staining (p D 0.053). Patients whose tumors expressed pMST1/2 nuc 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 (pMST1/2 cyt )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.KEYWORDS HER2-positive breast cancer; Hippo pathway; LATS 1/2; MST1/2; triple-negative breast cancer

Hippo-YAP1 Is a Prognosis Marker and Potentially Targetable Pathway in Advanced Gallbladder Cancer

“…Caspase-dependent cleavage or phosphorylation of its activation loop lead to MST1 translocation to the nucleus, which may be important for its pro-apoptotic functions [32]. MST1 activity can be affected by different molecular events, including a dysregulated crosstalk with oncogenic pathways and altered post-translational modifications at the protein level [10,[33][34][35]. In our study, the immunohistochemical evaluation of MST1 expression confirmed a diminished expression in GBC compared with CC.…”

“…The anticancer effects of MST1 have been reported for numerous types of cancer, including colorectal [34,35], breast [10,36,37] and lung cancers [38]. It should be noted that cytoplasmic expression of MST1 in cancer cells has been related with its function as a protective molecule acting in the canonical Hippo signaling pathway, through the inhibition of oncogenic YAP/TAZ [33]. In addition, MST1 can be cleaved by caspases which promotes its nuclear translocation, where it induces chromatin condensation and apoptosis [32].…”

The role of Hippo signal pathway in breast cancer metastasis

“…Therefore, MST1/2 may function as a potential predictive biomarker in HER2-positive and TN breast cancer patients. 71 The expression of TAZ/YAP was associated with inferior survival in male breast cancer patients. 72 The above studies support the notion that TAZ/YAP expression is correlated with tumor metastasis and patient outcomes.…”

TAZ functions as a tumor suppressor in multiple myeloma by downregulating MYC

“…As previously described, 24 YAP is also only weakly expressed or undetectable in HMCLs. In contrast, upstream regulators of the Hippo pathway, LATS1 and MST1, which are normally suppressed in solid tumors, [30][31][32] were expressed at higher levels in HMCLs compared with the lung cancer cell line A549 ( Figure 1C-D). These results suggest that the role of the Hippo pathway, particularly TAZ, in tumorigenesis is fundamentally different in MM and other hematological malignancies compared with their previously established oncogenic roles in solid tumors.…”