NOTCH3 Signaling Pathway Plays Crucial Roles in the Proliferation of ErbB2-Negative Human Breast Cancer Cells

Abstract

ErbB2-negative breast tumors represent a significant therapeutic hurdle because of a lack of effective molecular targets. Although NOTCH proteins are known to be involved in mammary tumorigenesis, the functional significance of these proteins in ErbB2-negative breast tumors is not clear. In the present study, we examined the expression of activated NOTCH receptors in human breast cancer cell lines, including ErbB2-negative and ErbB2-positive cell lines. Activated NOTCH1 and NOTCH3 proteins generated by ;-secretase were detected in most of the cell lines tested, and both proteins activated CSL-mediated transcription. Down-regulation of NOTCH1 by RNA interference had little or no suppressive effect on the proliferation of either ErbB2-positive or ErbB2-negative cell lines. In contrast, down-regulation of NOTCH3 significantly suppressed proliferation and promoted apoptosis of the ErbB2-negative tumor cell lines. Down-regulation of NOTCH3 did not have a significant effect on the ErbB2-positive tumor cell lines. Down-regulation of CSL also suppressed the proliferation of ErbB2-negative breast tumor cell lines, indicating that the NOTCH-CSL signaling axis is involved in cell proliferation. Finally, NOTCH3 gene amplification was detected in a breast tumor cell line and one breast cancer tissue specimen even though the frequency of NOTCH3 gene amplification was low (<1%). Taken together, these findings indicate that NOTCH3-mediated signaling rather than NOTCH1-mediated signaling plays an important role in the proliferation of ErbB2-negative breast tumor cells and that targeted suppression of this signaling pathway may be a promising strategy for the treatment of ErbB2-negative breast cancers.

The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction

“…The MDA-MB-231 line expresses Notch 1 and Notch 4. The MDA-MB-468 line expresses Notch 1 (Stylianou et al, 2006) and Notch 3 (Yamaguchi et al, 2008). The MCF-7 line expresses Notch 1 (Stylianou et al, 2006;Rizzo et al, 2008), Notch 3 (Yamaguchi et al, 2008) and Notch 4 (Sun et al, 2005).…”

“…It could be argued, however, that the stem cell-like properties of Notch 3 signaling and ALDH positivity exhibited by MARY-X (as it is triple negative) could be a manifestation of its basal origin rather than its IBC origin (Bertucci et al, 2006;Stylianou et al, 2006;Yamaguchi et al, 2008;Sansone et al, 2007a, b). IBC is a heterogeneous disease and it has been reported that the same molecular subtypes present in non-IBC are also present in IBC (Bertucci et al, 2005).…”

Downregulation of Dickkopf-1 is responsible for high proliferation of breast cancer cells via losing control of Wnt/β-catenin signaling

“…The enhanced and independent cell proliferation is an essential step in tumor metastasis [5] . Recent studies show that the signal transduction pathways, such as NOTCH3-mediated signaling, ErbB-mediated cascade, serum and glucocorticoid-inducible kinase (SGK)-mediated signaling, G proteincoupled receptor GPR40-mediated signaling and ERK/MAPK signaling, are involved in the regulation of breast cancer cell proliferation [6][7][8] . It has been reported that Wnt signaling plays an important role in regulation of cell proliferation in several cancers, such as prostate cancer, lung cancer, myeloma and www.chinaphar.com Zhou XL et al Acta Pharmacologica Sinica npg colon cancer [9][10][11][12] .…”

Inhibition of γ-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells

“…By providing an internally hydrophilic environment within the plasma membrane (Lazarov et al, 2006), g-secretase is responsible for cleaving more than 30 substrates, including amyloid precursor protein (APP), Notch (Mumm et al, 2000), ErbB4 (Ni et al, 2001), E-cadherin (Marambaud et al, 2002), CD44 (Lammich et al, 2002) and p75 (Schluesener et al, 1992), which regulate vital cell functions such as proliferation, cell cycle, cell adhesion and apoptosis. Interestingly, increased expression of Notch ligands, receptors, and/or downstream targets are highly associated in the pathogenesis of breast (Jones et al, 2004;Stylianou et al, 2006;Yamaguchi et al, 2008), brain (Purow et al, 2005), colon (Akiyoshi et al, 2008), cervical (Liu et al, 2007) pancreatic (Doucas et al, 2008) and skin cancers (Dang et al, 2006). Thus, the g-secretase complex may be a potential therapeutic target in a wide array of carcinomas.…”

“…In addition, Numb, a negative regulator of Notch signalling (McGill and McGlade, 2003), is significantly reduced in 50% of breast cancer tissues, inversely correlating with tumour size (Pece et al, 2004) and correlating with a poor prognosis (Colaluca et al, 2008). Inhibiting Notch signalling by overexpression of Numb reverts the transformed phenotype of MCF-7 cells (Stylianou et al, 2006), whereas silencing of Notch 3 inhibits proliferation and promotes apoptosis in ErbB2-negative breast cancer cell lines (Yamaguchi et al, 2008). Moreover, overexpression of Notch in non-tumourigenic breast epithelial cells induces transformation in vitro (Imatani and Callahan, 2000;Stylianou et al, 2006).…”