N-(2-Hydroxyphenyl)-2-propylpentanamide Modulates HDAC1 and GPER1 Expression in a Rodent Model of Triple-Negative...

Background: Triple-negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes due to its rapid growth, poor prognosis, and low response to chemotherapies owing to a lack of therapeutic targets and drug resistance. Histone deacetylases (HDACs) induce stromal changes that increase extracellular matrix density through the activity of cancer-associated fibroblasts (CAFs). HDACs are overexpressed in TNBC and have been linked to the activation and sustained activity of CAFs. Additionally, HDAC inhibitors decrease the fibroblastic activity. Objectives: We aimed to analyze the antifibrotic effect of the N-(2'-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), an inhibitor of the HDAC1, 6, and 8 (iHDAC) on TNBC. Methods: The TNBC (4T1) cell line was inoculated under the dorsal skin in mice to develop a TNBC tumor. CAF's activation was determined by measuring collagen-1 and alpha-smooth muscle actin (α-SMA), as well as their association with the G-protein-coupled estrogenic receptor (GPER1) and HDAC1 expression. Results: Dose of 20 mg/kg of HO-AAVPA decreased tumor fibrosis by inducing decreased collagen-1 and alpha-smooth muscle actin (α-SMA) levels and increased GPER1 expression. Moreover, HO-AAVPA reduced the activation and activity of CAFs. Conclusion: Our results support the notion that HDAC1 inhibition may be a novel approach to sensitizing resistant tumor cells to chemotherapy and radiotherapy by increasing GPER1 expression, and thus the use of antiproliferative GPER1 agonists/antagonists, at least in the early stages, without causing significant changes in liver function or morphological alterations.