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

• Published in: Oncogene Vol. 40; no. 16; pp. 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: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-04-2021; Nature Publishing Group
• Subjects: 13/1; 13/31; 13/51; 13/95; 14/63; 38/1; 631/532/71; 631/67/1347; 631/67/395; 64/60; 82/58; 96/1; AKT protein; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer cells; Care and treatment; Cell activation; Cell Biology; Cell migration; Cell self-renewal; Development and progression; Female; Gene expression; Genetic aspects; Health aspects; Heterografts; Human Genetics; Humans; Immunoprecipitation; Internal Medicine; Lymph nodes; Medicine; Medicine & Public Health; Membrane proteins; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastases; Metastasis; Mice; Neoplastic Stem Cells - metabolism; Oncogenes; Oncology; Phosphoproteomes; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Risk Factors; Stem cells; Tumorigenicity; Xenografts; Taiwan
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-021-01729-1

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.