Role of Erbin in ErbB2-dependent breast tumor growth

Abstract

ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2), a receptor tyrosine kinase of the ErbB family, is overexpressed in around 25% of breast cancers. In addition to forming a heterodimer with other ErbB receptors in response to ligand stimulation, ErbB2 can be activated in a ligand-independent manner. We report here that Erbin, an ErbB2-interacting protein that was thought to act as an antitumor factor, is specifically expressed in mammary luminal epithelial cells and facilitates ErbB2-dependent proliferation of breast cancer cells and tumorigenesis in MMTV-neu transgenic mice. Disruption of their interaction decreases ErbB2-dependent proliferation, and deletion of the PDZ domain in Erbin hinders ErbB2-dependent tumor development in MMTV-neu mice. Mechanistically, Erbin forms a complex with ErbB2, promotes its interaction with the chaperon protein HSP90, and thus prevents its degradation. Finally, ErbB2 and Erbin expression correlates in human breast tumor tissues. Together, these observations establish Erbin as an ErbB2 regulator for breast tumor formation and progression.ErbB2 | Erbin | HSP90 | breast cancer | stability T he human epidermal growth factor receptor (HER) family of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR, HER1, ErbB1), ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; HER2, neu), ErbB3 (HER3), and ErbB4 (HER4), has been implicated in tumor growth and progression. ErbB2, in particular, is overexpressed in around 25% of breast cancers, conferring high recurrence, malignant metastasis, and poor prognosis, (1, 2) and is also overexpressed in ovarian, stomach, and uterine tumors (3, 4). Upon ligand stimulation, ErbB receptors dimerize to activate downstream signaling (4). Unique in the ErbB family, ErbB2 does not have a ligand but is a preferred heterodimerization partner of other ErbB receptors in response to ligand stimulation. In mice, overexpression of ErbB2 or its activated form in mammary epithelium induces diffuse epithelial hyperplasia, mammary tumors, and lung metastases (5, 6). Unlike other ErbB members such as EGFR, which, upon activation, becomes internalized and sorted to lysosomes for degradation, ErbB2 is refractory to endocytosis and degradation (7,8). The underlying mechanisms of ErbB2 stability are not well characterized.Erbin is a cytoplasmic protein that contains leucine-rich repeats (LRR) and PSD95/Dlg1/zo-1 (PDZ) domain (thus named a LAP protein) (9, 10). Erbin interacts, via its single PDZ domain, specifically with ErbB2, but not with ErbB3, ErbB4, or EGFR (11,12). It is colocalized with ErbB2 at the basolateral membranes of epithelial cells (11). In vitro studies are inconsistent regarding the role of Erbin in cell proliferation and tumorigenesis. It was thought to act as a tumor suppressor by inhibiting TGFβ or Erk signaling (13-15). On the other hand, knockdown of Erbin in HT-29 colon cancer cells appears to inhibit the formation of multicellular tumor spheroids (16).Here we report that Erbin is exp...

Erbin loss promotes cancer cell proliferation through feedback activation of Akt-Skp2-p27 signaling

“…Erbin dysregulation has previously been reported in cervical tumors, colon carcinomas and breast carcinomas [12,13,20]. Here, we provide evidence to support the mechanistic connection between Erbin loss and aberrant Skp2-p27 axis, which coordinately drives cancer cells to uncontrolledly proliferate through cell cycle regulation.…”

“…A recent study form our group demonstrated that Erbin is significantly decreased or lost in cervical cancer tissues and loss of Erbin endows cervical cancer with resistance to anoikis by inhibiting STAT3 signaling [12]. Of note is that other group recently found that Erbin plays a positive role in ErbB2-dependent breast tumor growth [13]. In this regard, the role of Erbin in human cancer is conflicting.…”

Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway

“…Immunohistochemical (IHC) staining was performed as described previously(27). Tissue sections were incubated in 10 mM sodium citrate buffer (pH 6.0) at sub-boiling temperatures for 10 min, rinsed in PBS, and incubated with 10% normal goat serum to block non-specific staining.…”

Erbin and ErbB2 play roles in the sexual differentiation of the song system nucleus HVC in bengalese finches (Lonchura Striata var. domestica)

“…We recently identified male‐biased genes in the telencephalon of the Bengalese finch, including a Z chromosome gene erbin (ErbB2 interacting protein) and ErbB2 (a homolog of the avian erythroblastic leukemia viral oncogene homolog 2) (Sun et al, ). Both Erbin and ErbB2 have been reported to be involved in cell proliferation, survival, and differentiation through signaling pathways mediated by Erbin (mitogen‐activated protein kinases, MAPK; transforming growth factor β, TGF‐β; nuclear factor‐κB, NF‐κB) or by Erbb2 (extracellular regulated protein kinases, ERK or Ras‐Raf‐Mek‐Erk; protein kinase C, PKC) (Borg et al, ; Rangwala et al, ; Citri and Yarden, ; Zhou et al, ; Roskoski, ; Tao et al, ). Given the reported roles of erbin and erbb2 , we further wanted to know: (1) whether erbin and erbb2 expressions have sexual differences in the developing HVC, a song control nucleus in the Bengalese finch; (2) whether cell proliferation, and neuronal differentiation are affected after injections of erbin‐ or erbb2‐ interfering lentiviruses into the developing HVC and its overlying VZ (after erbin‐ or erbb2 knock‐down).…”

“…We recently identified male-biased genes in the telencephalon of the Bengalese finch, including a Z chromosome gene erbin (ErbB2 interacting protein) and ErbB2 (a homolog of the avian erythroblastic leukemia viral oncogene homolog 2) (Sun et al, 2010). Both Erbin and ErbB2 have been reported to be involved in cell proliferation, survival, and differentiation through signaling pathways mediated by Erbin (mitogen-activated protein kinases, MAPK; transforming growth factor b, TGF-b; nuclear factor-jB, NF-jB) or by Erbb2 (extracellular regulated protein kinases, ERK or Ras-Raf-Mek-Erk; protein kinase C, PKC) (Borg et al, 2000;Rangwala et al, 2005;Citri and Yarden, 2006;Zhou et al, 2012;Roskoski, 2014;Tao et al, 2014). Given the reported roles of erbin and erbb2, we further wanted to know:…”