The transdermal cream of Formestane anti-breast cancer by controlling PI3K-Akt pathway and the tumor immune microenvironment.

Background: Treatment of ER+ breast cancer with intramuscular formulation of Formestane (4-OHA) shrinks the tumor within weeks. Since the tedious way of intramuscular administration and side effects are not suited for adjuvant treatment, Formestane was withdrawn from the market. A new transdermal formulation of 4-OHA cream may overcome the defects and retain the effect of shrinking the breast cancer tumor. However, the effects of 4-OHA cream on breast cancer need further confirmatory studies. Methods: In this work, in vivo, the influence of 4-OHA cream on breast cancer was evaluated using the mode of 7,12-dimethylbenz(a)anthracene (DMBA) induced rat mammary cancer. We explored the common molecule mechanisms of action of 4-OHA cream and its injection formulation on breast cancer through RNA- sequencing-based transcriptome analysis and several biochemical experiments. Results: The results showed that the cream substantially reduced the entire quantity, size, and volum of tumors in DMBA-treated rats consistent with 4-OHA injection, and indicated that there were comprehensive signals involved in 4-OHA antitumor activity, such as ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and proteoglycans in cancer. In addition, we observed that both 4-OHA formulations could enhance immune infiltration, especially CD8+ T cells, B cells, natural killer cells, and macrophages infiltration, in the DMBA-induced mammary tumor tissues. The antitumor effects of 4-OHA partly depended on these immune cells. Conclusion: 4-OHA cream could inhibit breast cancer growth as its injection formulation and may provide a new way for neoadjuvant treatment of ER+ breast cancer.

Corrigendum: Proteome Analysis of USP7 Substrates Revealed Its Role in Melanoma Through PI3K/Akt/FOXO and AMPK Pathways.

[This corrects the article DOI: 10.3389/fonc.2021.650165.].

Proteome Analysis of USP7 Substrates Revealed Its Role in Melanoma Through PI3K/Akt/FOXO and AMPK Pathways.

The ubiquitin-specific protease 7 (USP7), as a deubiquitinating enzyme, plays an important role in tumor progression by various mechanisms and serves as a potential therapeutic target. However, the functional role of USP7 in melanoma remains elusive. Here, we found that USP7 is overexpressed in human melanoma by tissue microarray. We performed TMT-based quantitative proteomic analysis to evaluate the A375 human melanoma cells treated with siRNA of USP7. Our data revealed specific proteins as well as multiple pathways and processes that are impacted by USP7. We found that the phosphatidylinositol-3-kinases/Akt (PI3K-Akt), forkhead box O (FOXO), and AMP-activated protein kinase (AMPK) signaling pathways may be closely related to USP7 expression in melanoma. Moreover, knockdown of USP7 in A375 cells, particularly USP7 knockout using CRISPR-Cas9, verified that USP7 regulates cell proliferation in vivo and in vitro. The results showed that inhibition of USP7 increases expression of the AMPK beta (PRKAB1), caspase 7(CASP7), and protein phosphatase 2 subunit B R3 isoform (PPP2R3A), while attenuating expression of C subunit of vacuolar ATPase (ATP6V0C), and peroxisomal biogenesis factor 11 beta (PEX11B). In summary, these findings reveal an important role of USP7 in regulating melanoma progression via PI3K/Akt/FOXO and AMPK signaling pathways and implicate USP7 as an attractive anticancer target for melanoma.