Triple negative breast cancer (TNBC) is an aggressive breast cancer with historically poor outcomes, primarily due to the lack of effective targeted therapies. The tumor molecular heterogeneity of TNBC has been well recognized, yet molecular subtype driven therapy remains lacking. While neoadjuvant anthracycline and taxane-based chemotherapy remains the standard of care for early stage TNBC, the optimal chemotherapy regimen is debatable. The addition of carboplatin to anthracycline, cyclophosphamide, and taxane (ACT) regimen is associated with improved complete pathologic response (pCR). Immune checkpoint inhibitor (ICI) combinations significantly increase pCR in TNBC. Increased tumor infiltrating lymphocyte (TILs) or the presence of DNA repair deficiency (DRD) mutation is associated with increased pCR. Other targets, such as poly-ADP-ribosyl polymerase inhibitors (PARPi) and Phosphatidylinositol-3-kinase/Protein Kinase B/mammalian target of rapamycin (PI3K-AKT-mTOR) pathway inhibitors, are being evaluated in the neoadjuvant setting. This review examines recent progress in neoadjuvant therapy of TNBC, including platinum, ICI, PARPi, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) pathway targeted therapies, and novel tumor microenvironment (TME) targeted therapy, in addition to biomarkers for the prediction of pCR.

Acute intermittent porphyria (AIP) is a metabolic disorder characterized by a partial deficiency of the porphobilinogen deaminase (PBGD, EC 4.3

Fatty acid synthase (FASN) is highly expressed in breast carcinomas to support their continuous growth and proliferation, but has low expression level in normal tissues. Considerable interest has been developed in searching for novel FASN inhibitors as a therapeutic target for breast cancer. In present study, amentoflavone was isolated from Selaginella tamariscina, a traditional oriental medicine that has been used to treat cancer for many years, and was found to significantly inhibit the in vitro enzymatic activity of FASN at concentrations above 50 microM. Amentoflavone was also found to decrease fatty acid synthesis by the reduction of [(3)H]acetyl-CoA incorporation into lipids in FASN-overexpressed SK-BR-3 human breast cancer cells. Furthermore, this study showed that amentoflavone, at a concentration greater than 75 microM, increased the cleavage-activity of caspase-3 and poly (ADP-ribose) polymerase (PARP), and administration of pan-caspase inhibitor Z-VAD-FMK completely rescued the SK-BR-3 cells from PARP cleavages. The sequential internucleosomal DNA fragmentation in SK-BR-3 cells was observed at a concentration of 100 microM. A decrease in breast cancer cell growth was observed in SK-BR-3 cells at 12 and 24 h post treatment with 100 microM of amentoflavone, followed by a dramatic suppression after 48 h. The inhibition of cancer-growth by amentoflavone was dose-dependent, showing a slight reduction at 50 microM and significant reduction at concentrations of 75 and 100 microM. FASN-nonexpressed NIH-3T3 normal cell growth was not decreased by amentoflavone-treatment, both in time- and dose-dependent manners. These data provide evidence that amentoflavone isolated from S. tamariscina induced breast cancer apoptosis through blockade of fatty acid synthesis.

Somatic frameshift mutations in some genes containing coding mononucleotide repeats (cMNRs) are well known characteristics of tumors with high microsatellite instability (MSI-H). We identified 22 novel and 11 known target genes containing cMNRs with a length of 10 or more nucleotides by using a systematic database search. Frameshift mutation analysis was performed with these 33 genes in 39 MSI-H and 24 microsatellite stable (MSS) colorectal carcinomas by assessing the mobility shifts of PCR products in gel electrophoresis and by sequencing. All the 39 MSI-H colorectal carcinomas, except one, showed mutations in more than one gene, while no mutations were found in 24 MSS colorectal carcinomas. Of these MSI-H tumors, 11 genes were mutated in more than 40%. The most frequently mutated novel genes were MARCKS (72%), FLJ11383 (74%) and TAF1B (82%). Biallelic inactivation in MARCKS and FLJ11383 was also frequent in MSI-H tumors. The observed mutation frequency of the 11 known target genes was compatible with that found by previous studies. The very high frequency of mutations, biallelic mutations and the predicted truncation of protein products suggests that mutations of MARCKS, FLJ11383 and TAF1B are selected, and play a role in the tumorigenesis of MSI-H colorectal carcinomas.

No abstract