HDAC8 Activates AKT through Upregulating PLCB1 and Suppressing DESC1 Expression in MEK1/2 Inhibition-Resistant Cells.

Inhibition of the RAF-MEK1/2-ERK signaling pathway is an ideal strategy for treating cancers with NRAS or BRAF mutations. However, the development of resistance due to incomplete inhibition of the pathway and activation of compensatory cell proliferation pathways is a major impediment of the targeted therapy. The anthrax lethal toxin (LT), which cleaves and inactivates MEKs, is a modifiable biomolecule that can be delivered selectively to tumor cells and potently kills various tumor cells. However, resistance to LT and the mechanism involved are yet to be explored. Here, we show that LT, through inhibiting MEK1/2-ERK activation, inhibits the proliferation of cancer cells with NRAS/BRAF mutations. Among them, the human colorectal tumor HT-29 and murine melanoma B16-BL6 cells developed resistance to LT in 2 to 3 days of treatment. These resistant cells activated AKT through a histone deacetylase (HDAC) 8-dependent pathway. Using an Affymetrix microarray, followed by qPCR validation, we identified that the differential expression of the phospholipase C-ß1 (PLCB1) and squamous cell carcinoma-1 (DESC1) played an important role in HDAC8-mediated AKT activation and resistance to MEK1/2-ERK inhibition. By using inhibitors, small interference RNAs and/or expression vectors, we found that the inhibition of HDAC8 suppressed PLCB1 expression and induced DESC1 expression in the resistant cells, which led to the inhibition of AKT and re-sensitization to LT and MEK1/2 inhibition. These results suggest that targeting PLCB1 and DESC1 is a novel strategy for inhibiting the resistance to MEK1/2 inhibition.

The oncologic impact of hormone replacement therapy in premenopausal breast cancer survivors: A systematic review.

SYNOPSIS: This is the first systematic review to investigate the risk of recurrence in breast cancer survivors <50 years old who have used hormone replacement therapy (HRT). BACKGROUND: The risk of HRT in premenopausal breast cancer survivors is unclear. Due to the higher incidence of estrogen receptor negative tumours in women <50, the potential for HRT to promote breast cancer recurrence may differ from older age groups. METHODS: We performed a search of Medline, EMBASE and CINAHL through June 2016. For the observational studies relative risk (RR) and 95% confidence interval (CI) were calculated for the recurrence rate among HRT users and nonusers. A random effects model was used to estimate the combined RR using the Mantel-Haenszel method. RESULTS: Four papers satisfied our inclusion criteria. 3477 subjects were analyzed. On pooled meta-analysis of breast cancer recurrence in the observational studies, no significant association was found between HRT and risk of recurrence (RR 1.04 [95% CI 0.45, 2.41]). The randomized controlled trial (RCT) included found an increased risk of recurrence with HRT among women <50 (HR 1.56 [95% CI 1.1-2.2]). However, among women of all ages with an estrogen receptor negative tumour there was no significant difference in recurrence when compared to hormone receptor positive tumours (HR 1.15 [95% CI 0.7-1.8, p = 0.55]). DISCUSSION: This review on HRT in breast cancer survivors <50 revealed conflicting results between randomized and observational study data. Further studies are warranted to investigate the association between HRT and recurrence rates in younger breast cancer survivors.