COMMD3 loss drives invasive breast cancer growth by modulating copper homeostasis

Abstract

Background Despite overall improvement in breast cancer patient outcomes from earlier diagnosis and personalised treatment approaches, some patients continue to experience recurrence and incurable metastases. It is therefore imperative to understand the molecular changes that allow transition from a non-aggressive state to a more aggressive phenotype. This transition is governed by a number of factors. Methods As crosstalk with extracellular matrix (ECM) is critical for tumour cell growth and survival, we applied high throughput shRNA screening on a validated ‘3D on-top cellular assay’ to identify novel growth suppressive mechanisms. Results A number of novel candidate genes were identified. We focused on COMMD3, a previously poorly characterised gene that suppressed invasive growth of ER + breast cancer cells in the cellular assay. Analysis of published expression data suggested that COMMD3 is normally expressed in the mammary ducts and lobules, that expression is lost in some tumours and that loss is associated with lower survival probability. We performed immunohistochemical analysis of an independent tumour cohort to investigate relationships between COMMD3 protein expression, phenotypic markers and disease-specific survival. This revealed an association between COMMD3 loss and shorter survival in hormone-dependent breast cancers and in particularly luminal-A-like tumours (ER+/Ki67-low; 10-year survival probability 0.83 vs. 0.73 for COMMD3-positive and -negative cases, respectively). Expression of COMMD3 in luminal-A-like tumours was directly associated with markers of luminal differentiation: c-KIT, ELF5, androgen receptor and tubule formation (the extent of normal glandular architecture; p < 0.05). Consistent with this, depletion of COMMD3 induced invasive spheroid growth in ER + breast cancer cell lines in vitro, while Commd3 depletion in the relatively indolent 4T07 TNBC mouse cell line promoted tumour expansion in syngeneic Balb/c hosts. Notably, RNA sequencing revealed a role for COMMD3 in copper signalling, via regulation of the Na+/K+-ATPase subunit, ATP1B1. Treatment of COMMD3-depleted cells with the copper chelator, tetrathiomolybdate, significantly reduced invasive spheroid growth via induction of apoptosis. Conclusion Overall, we found that COMMD3 loss promoted aggressive behaviour in breast cancer cells.

Genome-wide associations with longevity and reproductive traits in U.S. rangeland ewes

“…As previously discussed, BMI1 has ties to the immune system through pathways related to the transcription factor NF-κB. The COMMD family member COMM domain containing 3 (COMMD3) has been recently identified as a regulator of human epidermal growth factor receptor 2 (HER2) endosomal trafficking ( Wang et al, 2023 ), and has potential roles in copper homeostasis in the progression of breast cancer ( Hancock et al, 2023 ). Expression of the gene SPAG6 is negatively correlated with prognosis for acute myeloid leukemia (AML) patients, and SPAG6 has been shown to interact with myosin 1D to increase expression of EGFR family within the context of AML ( Mu et al, 2022 ).…”

Disulfiram: A novel repurposed drug for cancer therapy

“…[ 27 , 29 ] Elevated Cu levels in tumor cells serve as a specific target for DSF, which binds tumor cellular copper and impairs the activities of Cu-dependent enzymes, leading to inhibition of cuproplasia (Cu-dependent cellular proliferation). [ 30 ] On the other hand, a high concentration of Cu in cancer cells causes cytotoxicity through oxidative stress or by inhibiting enzyme activity to induce specific copper-dependent cell death, called cuproptosis. [ 31 ] The Cu ionophore DSF facilitates increased Cu uptake into cancer cells, enabling DSF to specifically target cancer cells while sparing normal cells.…”

The mechanism of copper homeostasis and its role in disease

“…In a phase I clinical trial of metastatic solid tumor patients, it is reasonable to hypothesize that TM treatment reduced the growth or size of solid tumors by impairing neovascularization [71]. Moreover, treating COMMD3 low expressing cells with TM significantly counteracted disease progression and metastasis of breast cancer [72]. In addition, TM increased the median tumor formation time in mice from 234 days (untreated mice) to 460 days.…”