American Association for Cancer Research
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Figure S6 from Phosphodiesterase 3A Represents a Therapeutic Target that Drives Stem Cell–like Property and Metastasis in Breast Cancer

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posted on 2023-04-03, 16:03 authored by Na Hao, Wenzhi Shen, Renle Du, Shan Jiang, Junyong Zhu, Yanan Chen, Chongbiao Huang, Yi Shi, Rong Xiang, Yunping Luo

Figure S6 shows that the side effects of Cilostazol.

Funding

National Basic Research Program of China (973 Program)

National Natural Science Foundation of China

International Science and Technology Cooperation Programme

History

ARTICLE ABSTRACT

Considerable evidence suggests that as breast cancer progresses, genetic and epigenetic mechanisms contribute to the emergence of self-renewing cells (CSC), which may also arise as a consequence of metastasis. Although the molecular pathways that trigger stemness and metastasis are known, key molecular and mechanistic gaps in our understanding of these processes remain unclear. Here, we first screened the inflammation-associated stemness gene phosphodiesterase 3A (PDE3A) using a medium-throughput siRNA library, which was overexpressed in breast tumors and significantly correlated with clinical progression. PDE3A induced the inflammatory nuclear factor NFκB signaling pathway by suppressing cAMP/PKA, which promotes the expression of the stem cell marker OCT4. In addition, PDE3A also promoted the translocation of CCDC88A from the cytoplasm to nuclei, thereby boosting the invasion–metastasis cascade in breast cancer. Most importantly, the PDE3A-selective inhibitor cilostazol dramatically suppressed breast tumor growth and reduced metastasis to the lungs in xenograft breast cancer models, with minimum toxicity. Taken together, we show that PDE3A could predispose patients with breast cancer to metastases by acting as a mediator of cancer stemness. PDE3A is a potential therapeutic target for advanced breast cancer.