Cholesterol biosynthesis inhibitor RO 48-8071 reduces progesterone receptor expression and inhibits progestin-dependent stem cell-like cell growth in hormone-dependent human breast cancer cells

Abstract

Clinical trials and studies have shown that postmenopausal women undergoing combination hormone replacement therapy containing estrogen and progestin have an increased risk of breast cancer compared with women taking estrogen or placebo alone. Using animal models, we have previously shown that synthetic progestins, including medroxyprogesterone acetate (MPA), which is widely used clinically, accelerate breast cancer tumor growth and promote metastasis. Furthermore, we have found that MPA elevates CD44 protein expression and aldehyde dehydrogenase (ALDH) activity, two markers of cancer stem cells (CSCs), and increases mammosphere formation, another hallmark of stem cells, in hormone-dependent T47-D human breast cancer cells. Herein, we show that RO 48-8071 (RO), an inhibitor of cholesterol synthesis, reduced MPA-induced CD44 protein expression in two hormone-dependent human breast cancer cell lines, T47-D and BT-474. Because we have previously shown that MPA induction of CD44 is progesterone receptor (PR) dependent, we examined RO’s effects on PR protein and mRNA expressions in T47-D cells. PR mRNA levels remained unchanged after RO treatment; however, RO significantly reduced the protein expression of both PR receptor isoforms, PR-A and PR-B. Using the proteasome inhibitor MG-132, we demonstrated that RO decreases PR protein expression in T47-D cells via the proteasomal degradation pathway. Importantly, treatment of T47-D cells with RO abolished MPA-induced mammosphere formation. Based on our observations, we contend that RO may represent a novel means of preventing MPA-induced CSC expansion. RO could be used clinically to both treat and prevent hormone-dependent breast cancers, which represent the majority of human breast cancers. RO may also have clinical utility in reducing resistance to antihormone therapy.

https://researchopenworld.com/invited-commentary-proposing-potential-new-treatment-strategies-to-combat-breast-cancer-based-on-our-recently-published-manuscripts/#

“…RO 48-8071 (RO), inhibits 2, 3-oxidosqualene cyclase (OSC), a critical enzyme in the biosynthetic pathway leading to cholesterol production. RO significantly reduced the MPA-induced expression of CD44, lowered levels of PR which were elevated in response to MPA and abolished mammosphere formation [5,6]. The latter observation suggests that RO interferes with progestin-dependent enrichment of CSCs.…”

Lipid metabolism dynamics in cancer stem cells: potential targets for cancers

“…Some researchers have also demonstrated that synthetic progestins, such as medroxyprogesterone acetate (MPA), widely utilized in clinical practice, expedite the formation of breast tumorspheres while simultaneously increasing the activity of ALDH1A1 in CSCs and augmenting the tumorigenicity of CSCs ( Goyette et al, 2017 ). Furthermore, it has been found that cholesterol synthesis inhibitors can mitigate this undesirable induction of breast tumorspheres by MPA ( Liang et al, 2017 ).…”

Should oxidosqualene cyclase in the cholesterol biosynthetic pathway be considered an anti-cancer target?

“…In studies aimed at developing novel therapeutic techniques to combat hormone-dependent breast cancer, we found that RO decreased the expression of progesterone receptors in BT-474 and T-47D human breast cancer cells, and, furthermore, reduced levels of progestin-induced markers of cancer stem cells (CSCs), such as aldehyde dehydrogenase (ALDH), which are a hallmark of aggressive tumor growth, metastasis, and reappearance of cancer ( Liang et al, 2017 ). RO also reduced expression of estrogen receptor α (ERα), which is known to promote proliferation of hormone-dependent breast cancer cells, while inducing ERβ expression ( Liang et al, 2014 ).…”