The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer

Abstract

Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERα could sensitize ERα-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERα-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERα and increased therapeutic sensitivity of ERα-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer.

Histone Deacetylase Inhibitors: An Attractive Therapeutic Strategy Against Breast Cancer

“…In this study, FTY720 was given orally to mice in clinically accepted doses and, as a result, HDAC activity decreased and the evolution and development of breast tumors were diminished (110). They also found that the inhibitor sensitizes cells to tamoxifen and, in comparison with other HDAC inhibitors (e.g.…”

“…They also found that the inhibitor sensitizes cells to tamoxifen and, in comparison with other HDAC inhibitors (e.g. SAHA), it enhanced the sensitivity to the treatment (110).…”

The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases

“…FTY720 is phosphorylated in the nucleus by SphK2 and FTY720-phosphate, a potent class I HDAC inhibitor that facilitates fear extinction memory in mice (36). In addition, FTY720 also activates estrogen receptor (ER)- expression to enhance hormonal therapy for breast cancer (37).…”

Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival

“…Recent studies suggest that S1P generated from SphK2, may promote cancer cell proliferation and migration, suggesting SphK2 and S1P as potential therapeutic targets in cancer cell [21–23]. Our recent studies demonstrate that a selective SphK2 inhibitor K-145 reduces intracellular S1P [23], reduces specific histone acetylation in the nucleus of breast cancer cells [24], drastically attenuated breast cancer growth in a syngeneic mouse model [23]. Together, SphKs/S1P signaling is critical for growth and survival of estrogen receptor positive breast cancer cells, however the role of SphKs/S1P in TNBC and more importantly in metastatic breast cancer progression was not demonstrated before.…”

“…A selective and potent inhibitor of sphingosine kinase 1 (SphK1) PF-543 is not effective on original parental triple-negative MDA-MB-231 breast cancer cells to attenuate survival signaling but it markedly attenuated cell growth and PI3K/AKT, ERK & p38 MAP kinases survival signaling of lung metastatic variant LM2-4 human breast cancer cells. We found that SphK2, which is mainly localized in the nucleus of triple-negative MDA-MB-231 human breast cancer cells [24], it also essential for metastatic variant LM2-4 breast cancer cells growth and survival. Our studies demonstrated that triple-negative metastatic human breast cancer progression is dependent on SphKs/S1P signaling.…”