Estrogen Signaling Induces Mitochondrial Dysfunction-Associated Autophagy and Senescence in Breast Cancer Cells.

Khuloud Bajbouj,Jalal Taneera,Mawieh Hamad,Jasmin Shafarin

doi:10.3390/biology9040068

Abstract

Previous work has shown that although estrogen (E2) disrupts cellular iron metabolism and induces oxidative stress in breast and ovarian cancer cells, it fails to induce apoptosis. However, E2 treatment was reported to enhance the apoptotic effects of doxorubicin in cancer cells. This suggests that E2 can precipitate anti-growth effects that render cancer cells more susceptible to chemotherapy. To investigate such anti-growth non-apoptotic, effects of E2 in cancer cells, MDA-MB-231 and MCF-7 cells were evaluated for the expression of key autophagy and senescence markers and for mitochondrial damage following E2 treatment. Treated cells experienced mitochondrial membrane depolarization along with increased expression of LC3-I/II, Pink1 and LAMP2, increased LC3-II accumulation and increased lysosomal and mitochondrial accumulation and flattening. E2-treated MCF-7 cells also showed reduced P53 and pRb780 expression and increased Rb and P21 expression. Increased expression of the autophagy markers ATG3 and Beclin1 along with increased levels of β-galactosidase activity and IL-6 production were evident in E2-treated MCF-7 cells. These findings suggest that E2 precipitates a form of mitochondrial damage that leads to cell senescence and autophagy in breast cancer cells.

Highlights

Numerous studies have shown that estrogen (17β-estradiol; E2) induces tumorigenesis in mammals and increases the risk of breast and ovarian cancer in humans [1,2,3,4]
These findings suggest that E2 precipitates a form of mitochondrial damage that leads to cell senescence and autophagy in breast cancer cells
E2 treatment induces mitochondrial accumulation and autophagy in breast cancer cells: Several previous studies have reported on the ability of E2 to disrupt intracellular iron metabolism and to induce oxidative stress in breast cancer cells [15,16]

Summary

Introduction

Numerous studies have shown that estrogen (17β-estradiol; E2) induces tumorigenesis in mammals and increases the risk of breast and ovarian cancer in humans [1,2,3,4]. That said, mounting evidence suggest that E2 signaling precipitates anti-cancer effects in E2-responsive cancers of the breast, ovaries, uterus and liver. High-dose E2 treatment was successfully used against metastatic breast cancer in postmenopausal women for decades before the introduction of selective estrogen receptor modulators (SERMs) in the 1970s [5]. Clinical trials that evaluated the efficacy of tamoxifen versus high dose diethylstilbestrol (DES) against metastatic breast cancer have shown comparable clinical outcomes [6]. E2 replacement therapy was reported to reduce the incidence of invasive breast cancer in postmenopausal women with prior hysterectomy [8]. Differences in the incidence of hepatocellular carcinoma, being 2–4 times higher in males than in females [9,10,11], has been attributed to the protective effects of E2 [12]

Methods

Results

Discussion

Conclusion