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Context.--Breast cancer with low (1%-10%) estrogen receptor (ER) expression (ER-low positive) constitutes a small portion of invasive breast cancers, and the treatment strategy for these tumors remains debatable. Objective.--To characterize the features and outcomes of ER-low positive patients, and clarify the clinical significance of FOXC1 and SOX10 expression in ER-low positive/HER2-negative tumors. Design.--Among 9082 patients diagnosed with primary invasive breast cancer, the clinicopathologic features of those with ER-low positive breast cancer were characterized. FOXC1 and SOX10 mRNA levels were analyzed in ER-low positive/HER2-negative cases from public data sets. The expression of FOXC1 and SOX10 in ER-low positive/HER2-negative tumors was evaluated by immunohistochemistry. Results.--The clinicopathologic study of ER-low positive tumors indicated more aggressive characteristics compared with those tumors with ER >10%, while they had more overlapping features with ER-negative tumors irrespective of the HER2 status. The intrinsic molecular subtype of ER-low positive cases with high FOXC1 and SOX10 mRNA expression was more likely to be nonluminal. Among the ER-low positive/HER2-negative tumors, 56.67% (51 of 90) and 36.67% (33 of 90) were positive for FOXC1 and SOX10, respectively, which was significantly positively correlated with CK5/6 expression. In addition, the survival analysis demonstrated no significant difference between patients who received and who did not receive endocrine therapy. Conclusions.--ER-low positive breast cancers biologically overlap more with ER-negative tumors. ER-low positive/HER2-negative cases demonstrate a high rate of FOXC1 or SOX10 expression, and these cases might be better categorized as a basal-like phenotype/subtype. FOXC1 and SOX10 testing may be used for the intrinsic phenotype prediction for ER-low positive/HER2-negative patients. doi: 10.5858/arpa.2022-0370-OA, Invasive breast cancer is a clinically heterogeneous disease that can be classified into 4 intrinsic subtypes based on the molecular profile. (1) However, the cost and availability of molecular profiling [...]

N7-methylguanosine (m7G) is one of the most common post-transcriptional epigenetic modifications. Different m7G methyltransferases (writers) load the m7G-cap at the 5'-terminal or inside the RNAs. For example, writers such as methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4) and Williams-Beuren syndrome chromosome region 22 (WBSCR22) have been reported in mammals to promote cell proliferation, EMT, and chemoresistance in massive quantities of cancers. The underlying mechanism includes modulating the RNA secondary structure, preventing RNA degradation from exonucleases, and improving codon-dependent translation. However, some studies have shown that in colorectal and lung cancers, m7G inhibits tumor progression. m7G binding proteins (readers), such as eukaryotic translation initiation factor 4E (eIF4E), promote the efficiency of cap-dependent translation and accelerate the cell cycle to improve cancer progression. Due to the more profound understanding of m7G regulatory proteins in cancer, numerous studies aim to investigate the clinical efficiency of m7G-targeted therapy. eIF4E antisense oligonucleotide drug (4EASO) and Ribavirin are the most mature trials that competitively inhibit the binding of eIF4E to m7G-cap. These drugs have encouraging results in halting cancer progression and improving prognosis, including AML and non-small cell lung cancer, which provide a promising perspective for developing more m7G-targeted drugs. In the future, we look forward to an ongoing investigation into the role of m7G modification in tumors and drug resistance to m7G-related therapies to be solved. Therefore, the clinical application would be put into practice as soon as possible., Competing Interests: None., (AJCR Copyright © 2023.)