Activated ERβ?-induced breast cancer metastasis via TRPV1 in 4T1?-bearing mice

摘要

Breast cancer is the most common cancer in females It is known that cancer-induced death is due to the metastasis of primary tumor cells to secondary sites Asian women usually suffer from breast cancer in the perimenopausal period The breast cancer patients during the perimenopausal period exhibit a positive association between node metastasis and ERβ expression Clinical data indicated that the increased tumor aggressiveness is positively associated with serum calcium levels Extracellular Ca2+ influx through Ca2+ permeable ion channels is involved in breast cancer progression Transient receptor potential channels (TRP) channels on the plasma membrane are responsible for transporting extracellular calcium into the cell Thus the purpose of this study was to determine whether activation of ERβ by DHEA induced breast cancer metastasis via TRPV1 Accordingly two research aims were proposed The first aim was to assess whether DHEA played a role in hormone imbalance as in the perimenopausal period which accelerated the formation of ERβ+ breast cancer in chapter 2 The second aim was to determine whether activation of ERβ by DHEA caused the migration of 4T1/Luc+ breast tumor cells via TRPV1 in Chapter 3 In aim 1 our data showed that E2 and DHEA increased the number of migrated cells; testosterone and A-dione did not affect the number of migrated cells In premature male mice E2 and DHEA increased the total density of 4T1 cells-containing tumors in the intact group but not in the castrated group However in premature female mice E2 and DHEA did not increase the tumor density in the intact group but did increase the density in the ovariectomized group A daily treatment of E2 for 10 days E2 and that of DHEA for 14 days increased the total density of 4T1 cells-containing tumor in mature OVX female mice to a greater extent than that in mature intact mice In aim 2 Western blot analysis showed the existence of ERβ and TRPV1 in 4T1 cells In vivo imaged indicated that E2 and DHEA-induced metastasis is ERβ-dependent Analysis of both cell morphology and intensity of calcium fluorescence showed a positive association with Cap (TRPV1 activator)-increased migrated cells CapZ (TRPV1 blocker) and RHC (DAG lipase inhibitor) decreased the number of migrated cells by E2 and DHEA However PHTPP did not inhibit the number of migrated cells by Cap and OAG (TRPV1 endogenous activator) The10-day treatment with E2 and 14-day treatment with DHEA promoted the breast cancer metastasis and enhanced the relative abundance of ERβ protein CapZ inhibited the increase of cancer metastasis and ERβ expression by an ERβ activator Taken together these results suggest that alterations of both cell morphology and intracellular calcium concentrations are involved in ERβ-mediated and TRPV1-induced breast cancer progression Abnormal elevation of DHEA in perimenopausal period may activate ERβ open TRPV1 and accelerate calcium–dependent tumor development

獎項日期	2014 8月 27
原文	English
監督員	Mei-Ling Tsai (Supervisor)