Expression of tripartite motif-containing protein 28 in primary breast carcinoma predicts metastasis and is involved in the stemness, chemoresistance, and tumor growth

Abstract

The prediction of who develops metastasis has been the most difficult aspect in the management of breast cancer patients. The lymph node metastasis has been the most useful predictor of prognosis and patient management. However, a good proportion of patients with lymph node positivity remain disease free for 5 years or more, while about a third of those who were lymph node negative develop distant metastasis within the same period. This warrants a robust biomarker(s), preferably gene expression based. In order to elucidate gene-based biomarkers for prognosis of breast cancers, gene expression profiling of primary tumors and follow-up for over 5 years has been performed. The analysis revealed a network of genes centered around the tripartite motif-containing protein 28 as an important indicator of disease progression. Short hairpin RNA-mediated knockdown of tripartite motif-containing protein 28 in breast cancer cells revealed a decreased expression of epithelial-to-mesenchymal transition markers and increased expression of epithelial markers, decreased migration and invasion, and increased chemosensitivity to doxorubicin, 5-fluorouracil, and methotrexate. Furthermore, knockdown of tripartite motif-containing protein 28 resulted in the decrease of stemness as revealed by sphere formation assay as well as decreased expression of CD44 and Bmi1. Moreover, tripartite motif-containing protein 28 knockdown significantly reduced the tumor size and lung metastasis in orthotopic tumor xenograft assay in immunocompromised mice. The tumor size was further reduced when these mice were treated with doxorubicin. These data provide evidence for tripartite motif-containing protein 28 as a biomarker and a potential therapeutic target for breast cancer.

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

“…The detailed study of how these coregulators impact in maintaining this 3D structure will surely provide novel druggable targets that may better block FGF2‐induced MYC transcription. TRIM28 has been associated with a metastatic signature, stemness and increased breast cancer growth . STAT1 has been recently described as a SRC1‐partner able to activate gene expression in endocrine‐resistant cells, while STAT3 is a well‐known PR interactor .…”

A unique subset of low-risk Wilms tumors is characterized by loss of function of TRIM28 (KAP1), a gene critical in early renal development: A Children’s Oncology Group study

“…TRIM28 is critical for early differentiation and development [12]. A number of reports have also associated overexpression of TRIM28 with aggressiveness or poor outcome in adult cancers, specifically in breast, gastric, pancreatic, and brain tumors [26–29], although the mechanisms proposed are varied and perplexing [30].…”

Prognostic significance of TRIM28 expression in patients with breast carcinoma

“…In addition, TRIM28 acts directly with TWIST1 to stabilize it, and then enhances EMT to promote breast cancer metastasis [ 12 ]. Another report verified that TRIM28 is involved in the stemness, chemotherapy resistance, and tumorigenesis in BC [ 13 ]. However, in the clinical context, the correlation between TRIM28 expression and prognosis of BC remains obscure.…”