HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women

Abstract

Background: Breast cancer in very young women (BCVY) defined as <35 years old, presents with different molecular biology than in older patients. High HDAC5 expression has been associated with poor prognosis in breast cancer (BC) tissue. We aimed to analyze HDAC5 expression in BCVY and older patients and their correlation with clinical features, also studying the potential of HDAC5 inhibition in BC cell lines. Methods: HDAC5 expression in 60 BCVY and 47 older cases were analyzed by qRT-PCR and correlated with clinical data. The effect of the HDAC5 inhibitor, LMK-235, was analyzed in BC cell lines from older and young patients. We performed time and dose dependence viability, migration, proliferation, and apoptosis assays. Results: Our results correlate higher HDAC5 expression with worse prognosis in BCVY. However, we observed no differences between HDAC5 expression and pathological features. Our results showed greatly reduced progression in BCVY cell lines and also in all triple negative subtypes when cell lines were treated with LMK-235. Conclusions: In BCVY, we found higher expression of HDAC5. Overexpression of HDAC5 in BCVY correlates with lower survival rates. LMK-235 could be a potential treatment in BCVY.

Insights Into the Function and Clinical Application of HDAC5 in Cancer Management

“…LMK-235, a selective HDACi showed preferable interactions with the catalytic zinc ion of class IIA HDACs, was illustrated to decrease phosphohistone H3 and Ki-67 levels in pancreatic neuroendocrine tumors (pNETs) while inducing pNET cell apoptosis and histone H3 acetylation, making it an effective targeted therapy for pNET that indirectly antagonizes the activity of HDAC4/5 ( 125 ). Similar findings were reported in breast ( 20 , 65 ) and lung ( 93 ) cancers. However, LMK-235 induced HDAC5 expression in UC cells, indicating that HDAC5 is not a suitable therapeutic target in UC ( 132 ).…”

“…HDAC5 protein is expressed in lung, brain, myocardium, skeletal muscle, and placenta, and accumulating evidence indicates that it has variable expression and functions in different types of tumor: HDAC5 is overexpressed in breast cancer ( 19 , 20 ), hepatocellular carcinoma (HCC) ( 21 ), lung cancer ( 22 ), pancreatic neuroendocrine cancer(pNET) ( 23 ) and colorectal cancer(CRC) ( 24 ). In contrast, although HDAC5 was shown to induce tissue invasion of gastric cancer cells ( 25 ), gene expression profiles of histone modifiers indicate that HDAC5 is downregulated in gastric cancer ( 26 ) ( Table 1 ).…”

Fentanyl Inhibits Lung Cancer Viability and Invasion via Upregulation of miR-331-3p and Repression of HDAC5

“…HDAC5 is a well-known oncogene in numerous cancer types including lung cancer, e.g., HDAC5 level is increased in LCSCs, 32 HDAC5 induces the malignancy in NSCLC, 33 HDAC5 increases the cell proliferation and invasion in lung cancer, 34 HDAC5 is a predictor for poor clinical outcomes in pancreatic neuroendocrine tumor, 35 HDAC5 inhibitors act as potential therapies for young women with breast cancer. 36 However, the relation between miR-331-3p and HDAC5 has not been investigated until the conduction of the present study. In the present study, HDAC5 expression was higher in NSCLC cell lines than in BEAS-2B, which was reversed by fentanyl, the findings first indicated the potential relation between fentanyl and HDAC5 in the progression of NSCLC.…”

Pan-cancer analysis reveals unique molecular patterns associated with age

“…While clinical studies have not assessed differential sensitivity in young and old age groups, our analyses suggest that young patients could exhibit enhanced sensitivity to such treatment regimens. Recent work by Oltra et al shows that HDAC5 inhibition differentially induces apoptosis in breast cancer cell lines sourced from young patients(Oltra et al, 2020). Epigenomic reprogramming of young breast cancer patients results in age-acceleration at the transcriptional level as well, thereby causing gross functional alterations.…”