Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Abstract

Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor-positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro-and anti-angiogenic factors. VEGF is a proangiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-a and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies.

Ethanol-Extracted Cameroonian Propolis Counteracts Tamoxifen-Induced Endometrial Hyperplasia by Modulating Apoptosis and Proliferation-Regulating Proteins in the Ovaries of Intact Wistar Rats

“…is observation is in line with the increase in endometrial height. A significant (p < 0.05) increase in PCNA and VEGF expression was also reported by Karlsson et al [29] and Golderg et al [30], respectively, in tamoxifeninduced endometrial hyperplasia condition. e significant underexpression of PCNA (p < 0.05), Bcl-2 (p < 0.05), and VEGF (p < 0.05 at 50 mg/kg and p < 0.01 at 150 mg/kg) proteins and the significant overexpression of Bax (p < 0.05) and caspase-3 (p < 0.05 at 50 mg/kg andp < 0.01 at 150 mg/ kg) proteins in the endometrium following EECP treatment just like the pure antiestrogen fulvestrant are in agreement with the results of endometrial height, thus suggesting that EECP acted by inhibiting cell proliferation and triggering apoptosis.…”

The Role of PEDF in Reproductive Aging of the Ovary

“…Our finding of an elevated concentration of VEGF protein in the FF of RA patients, in accordance to the literature [ 44 , 45 ], point to a gene-specific mechanism and not a general property of aging. VEGF elevation, along with PEDF reduction, intensified the inverted relationship between PEDF and VEGF, as demonstrated in various models [ 30 , 46 , 47 ]. Consequently, the calculated PEDF/VEGF protein ratio is significantly decreased in RA patients, and inversely correlated with patients’ age, suggesting an impaired angiogenic balance at the onset of ovarian aging.…”

Pharmacodynamic structure of deer antler base protein and its mammary gland hyperplasia inhibition mechanism by mediating Raf-1/MEK/ERK signaling pathway activation

“…Tamoxifen, the main treatment drug for MGH, can only be used as a short-term treatment for MGH owing to its side effects of menstrual irregularities, and susceptibility to uterine hyperplasia and endometrial cancer. 22 Therefore, the identification of natural, effective, and safe anti-MGH drugs from Chinese medicine has become a focal point for research studies in recent years. Deer antler base is an animal herb that has been used clinically for Food & Function Paper thousands of years in the treatment of MGH.…”