Transmembrane and coiled-coil domain family 3 (TMCC3) regulates breast cancer stem cell and AKT activation

Cancer stem cells (CSC) play a pivotal role in cancer metastasis and resistance to therapy. Previously, we compared the phosphoproteomes of breast cancer stem cells (BCSCs) enriched subpopulation and non-BCSCs sorted from breast cancer patient-derived xenograft (PDX), and identified a function unkno...

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Bibliographic Details
Published in:Oncogene 2021-04, Vol.40 (16), p.2858-2871
Main Authors: Wang, Ya-Hui, Chan, Yu-Tzu, Hung, Tsai-Hsien, Hung, Jung-Tung, Kuo, Ming-Wei, Wang, Sheng-Hung, Huang, Yenlin, Lin, Yu-Ju, Chen, Shin-Cheh, Yu, Jyh-Cherng, Wu, Jen-Chine, Yu, John, Yu, Alice L
Format: Article
Language:English
Subjects:
AKT protein
Animals
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer cells
Care and treatment
Cell activation
Cell migration
Cell self-renewal
Development and progression
Female
Gene expression
Genetic aspects
Health aspects
Heterografts
Humans
Immunoprecipitation
Lymph nodes
Membrane proteins
Membrane Proteins - genetics
Membrane Proteins - metabolism
Metastases
Metastasis
Mice
Neoplastic Stem Cells - metabolism
Oncogenes
Phosphoproteomes
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Risk Factors
Stem cells
Tumorigenicity
Xenografts
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Summary:Cancer stem cells (CSC) play a pivotal role in cancer metastasis and resistance to therapy. Previously, we compared the phosphoproteomes of breast cancer stem cells (BCSCs) enriched subpopulation and non-BCSCs sorted from breast cancer patient-derived xenograft (PDX), and identified a function unknown protein, transmembrane and coiled-coil domain family 3 (TMCC3) to be a potential enrichment marker for BCSCs. We demonstrated greater expression of TMCC3 in BCSCs than non-BCSCs and higher expression of TMCC3 in metastatic lymph nodes and lungs than in primary tumor of breast cancer PDXs. TMCC3 silencing suppressed mammosphere formation, ALDH activity and cell migration in vitro, along with reduced tumorigenicity and metastasis in vivo. Mechanistically, we found that AKT activation was reduced by TMCC3 silencing, but enhanced by TMCC3 overexpression. We further demonstrated that TMCC3 interacted directly with AKT through its 1-153 a.a. domain by cell-free biochemical assay in vitro and co-immunoprecipitation and interaction domain mapping assays in vivo. Based on domain truncation studies, we showed that the AKT-interacting domain of TMCC3 was essential for TMCC3-induced AKT activation, self-renewal, and metastasis. Clinically, TMCC3 mRNA expression in 202 breast cancer specimens as determined by qRT-PCR assay showed that higher TMCC3 expression correlated with poorer clinical outcome of breast cancer, including early-stage breast cancer. Multivariable analysis identified TMCC3 expression as an independent risk factor for survival. These findings suggest that TMCC3 is crucial for maintenance of BCSCs features through AKT regulation, and TMCC3 expression has independent prognostic significance in breast cancer. Thus, TMCC3 may serve as a new target for therapy directed against CSCs.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-021-01729-1