Abstract
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.
Highlights
Breast cancer is the most common cancer among women worldwide
In our previous phosphoproteomic analysis of breast cancer stem cells (BCSCs) and non-BCSCs sorted from BC0145 patient-derived xenograft (PDX), the functions of ~21% of 455 phosphoproteins upregulated in BCSCs, including transmembrane and coiled-coil domain family 3 (TMCC3), were unknown (Fig. 1a) [15]
In our previous comparative phosphoproteomic analysis of BCSCs and non-BCSCs, we found a function unknown protein, TMCC3 to be expressed at higher level in BCSCs than non-BCSCs [15]
Summary
Transmembrane and coiled-coil domain family 3 (TMCC3) regulates breast cancer stem cell and AKT. These CSCs possessed the capacity for self-renewal, differentiation, and displayed resistance to chemotherapeutic agents and radiation, which might contribute to tumor relapse years after the clinical remission [6]. The TMCC family consists of three putative proteins (TMCC1–3) that are conserved from nematode to human [16]. TMCC3 is first cloned from human normal brain tissue. It is predicted as an integral membrane protein and localized in ER [17, 20]. We provide first evidence for the important roles of TMCC3 in self-renewal, metastasis, and tumorigenicity of BCSCs and AKT activation
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