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The Role of Progesterone and Estrogen in Breast Cancer Bone Metastasis Mediated by RANKL and Its Receptors

Author: LiuZuo
Tutor: WangShui
School: Nanjing Medical University
Course: Department of General Surgery
Keywords: Progesterone Estrogen Breast Cancer Receptor activator of nuclear factor κB pathway Breast cancer bone metastasis
CLC: R737.9
Type: Master's thesis
Year: 2011
Downloads: 88
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Abstract

Solid tumor of bone tissue is relatively common site of distant metastasis, especially in advanced breast cancer patients, the incidence of bone metastases close to 70%. Histological studies confirmed the majority of breast cancer bone metastasis are broken bone metastases, these metastases formation and osteoclast number and functions are closely related. Breast cancer bone metastasis can cause many severity of skeletal-related disorders, such as intractable pain, hypercalcemia. Pathological fractures and spinal cord compression and so on. Breast cancer patients with bone metastases in the average survival time after diagnosis is only 2-3 years. Seriously affected bone metastases of breast cancer patients' quality of life and survival time. However, breast cancer bone metastasis molecular mechanism is not clear so far. Recent studies have found that the number of new cell factor: receptor activator of nuclear factor κB ligand (RANKL, receptor activator of NF-κB ligand) and its functions receptor (RANK) and competitive receptor (OPG) and bone tissue remodeling and metabolic closely related. RANKL / RANK / OPG pathway can regulate osteoclast formation, thus affecting the process of bone resorption. RANKL is mainly expressed on the surface of osteoblasts, the factor may regulate osteoclast formation, function and survival ability. RAKNL combined with the receptor RANK, followed by activation of RANK, play a role. The OPG as a soluble TNF (Tumor necrosis factor, tumor necrosis factor), competitive binding with RANK RANKL, thereby regulating the function of RANKL. RANKL / RANK / OPG in a variety of solid tumors of bone metastases formation process plays an important role. Recently, some studies show that RANKL may mediate progesterone-induced proliferation of breast tissue and breast tumor formation. In addition RANKL can also adjust the mammary stem cell side population cells in mammary epithelial component. Estrogen and progesterone in breast tissue development and maturation process has played an irreplaceable role, but long-term exposure to these hormones and breast cancer, but are closely linked. In order to study progesterone and estrogen on breast cancer cell lines of different RANKL and its receptor (RANK, OPG) regulation of the expression, we will Exponentially growing breast cancer cell line T47D, MCF-7 and MDA-MB- 231 cells were seeded in 6-well culture plates, the cells were treated with 1 × 10 ~ 6M concentration of progesterone or 1 × 10 ~ 7M concentrations of estrogen stimulation for 24 hours. Using real-time quantitative real-time PCR technique in breast cancer cell lines were measured RANKL, RANK, OPG and progesterone receptor (PR) expression. Experimental results show that progesterone can significantly improve the T47D and MCF-7 cells the expression of RANKL. Progesterone and estrogen after, RNAK in breast cancer cell lines T47D and MCF-7 was significantly decreased. However, progesterone and estrogen for OPG in T47D and MCF-7 cells in the regulation of the expression is not very large. Compared with control group, 4T1 mouse breast cancer cell lines and human breast cancer cell line MDA-MB-231 cells after treatment 1μg/ml sRANKL, can be formed more mammosphere, the results suggest that breast cancer can be increased RANKL stem cell side population ratio. In addition, we found that the migration test RANKL can induce cancer cells MDA-MB-231 cells in the culture medium containing the migration of RANKL. In animal experiments, we injected through the left ventricle to complete mouse breast cancer bone metastasis model. One day after injection in the left ventricle, we passed subcutaneously, different experimental groups were given progesterone (P group) or RU486 (progesterone antagonist, RU group) treated mice were injected subcutaneously 100μl and give activated charcoal purified corn oil as blank control group. Experimental results show that the mice compared group P, RU mice have weaker bone metastasis density signal. However, RU group P group and the probability of occurrence of bone metastases, but the difference was not statistically significant. In summary, RANKL and its receptor in T47D and MCF-7 cell lines expressed by progesterone and estrogen regulation. Secondly, RANKL may stimulate breast cancer stem cells have the side population growth functions and the ability to induce breast cancer cell migration. Furthermore, RU486 inhibits RANKL-mediated bone metastasis of breast cancer cells. These results suggest that progesterone and estrogen and its receptor may be affected through RNAKL bone metastasis of breast cancer cells.

The Role of Progesterone and Estrogen in Breast Cancer Bone Metastasis Mediated by RANKL and Its Receptors

Abstract

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