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研究生：	古曉霖 Gu, Siao-Lin
論文名稱：	活化雌激素受體貝他透過辣椒素受器促進4T1乳癌細胞於小鼠體內之轉移 Activated ERβ-induced breast cancer metastasis via TRPV1 in 4T1-bearing mice
指導教授：	蔡美玲 Tsai, Mei-Ling
學位類別：	碩士 Master
系所名稱：	醫學院 - 生理學研究所 Department of Physiology
論文出版年：	2014
畢業學年度：	102
語文別：	英文
論文頁數：	54
中文關鍵詞：	乳癌、雌激素受體貝它、辣椒素通道
外文關鍵詞：	breast cancer, estrogen receptor β, TRPV1
相關次數：	點閱：91 下載：0
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在女性癌症病人中，乳癌是最常見的一種癌症，乳房惡性腫瘤的轉移會導致癌症的死亡率提高。乳癌的發生率受到雌激素 (E2) 濃度的影響，但是亞洲女性的乳癌發生率竟集中於雌激素逐漸降低的停經前後45-55歲。根據臨床結果顯示45-55歲的乳癌患者中，只表現雌激素受體貝它 (ERβ) 的乳癌細胞和高度轉移淋巴結的情況呈現正相關。此外，另一項臨床數據指出45-55歲的惡性乳癌患者的血液中含有較高濃度的鈣離子 (Ca2+)。然而，目前並不清楚雌激素受體貝它 (ERβ) 和辣椒素鈣離子通道 (TRPV1) 在45-55歲的乳癌患者中所扮演的角色。因此本篇研究分為兩個部份:第一部分是探討荷爾蒙不平衡在停經前後45-55歲的乳癌患者中所扮演的角色;第二部份是探討雌激素受體貝它 (ERβ) 和辣椒素鈣離子通道 (TRPV1) 在惡性乳癌中所扮演的角色。在第一部分的研究中，細胞遷移實驗結果顯示E2和dehydroepiandrosterone (DHEA) 提升4T1 (ERα-/ERβ+) 乳癌細胞爬行的數目，testosterone和androstenedione (A-dione) 不影響乳癌細胞爬行的數目。在腹腔注射E2 和DHEA導致的乳癌細胞擴散實驗中，正常公鼠比去睪丸公鼠的癌細胞擴散面積大；去卵巢母鼠比正常母鼠的癌細胞擴散面積大。另一方面，注射E2 和DHEA後，成熟去卵巢母鼠的癌細胞擴散面積比未成熟去卵巢母鼠的癌細胞擴散面積大。再者，注射10天E2和14天DHEA皆會顯著增加癌細胞擴散面積。在第二部份的研究中，4T1乳癌細胞表現ERβ和TRPV1。動物實驗結果顯示，E2和DHEA皆可活化ERβ導致癌細胞擴散並提升癌細胞轉移率。細胞實驗結果顯示活化TRPV1使得癌細胞型態從圓形變為紡錘狀、細胞內鈣離子濃度提高以及癌細胞爬行數目增加。接著探討ERβ和TRPV1 兩者之間的關係。細胞實驗結果顯示，TRPV1拮抗劑 (CapZ和RHC) 會抑制E2和DHEA活化ERβ導致的細胞型態改變、細胞內鈣離子濃度以及癌細胞爬行數目。ERβ拮抗劑 (PHTPP) 不會影響OAG和Cap活化TRPV1導致的細胞型態改變、細胞內鈣離子濃度以及癌細胞爬行數目。動物實驗結果顯示，TRPV1拮抗劑 (CapZ)會抑制E2和DHEA活化ERβ導致的癌細胞擴散和轉移率。本研究實驗結果推論DHEA在停經前後45-55歲的乳癌患者中扮演一個很重要的角色。E2和DHEA活化ERβ導致的惡性乳癌細胞擴散可能經由TRPV1的臨床藥物獲得改善。

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.

中文摘要……………………………………………………………………………I
Abstract……………………………………………………………………………..III
誌謝…………………………………………………………………………………V
目錄………………………………………………………………………………VI
LIST OF FIGURES………………………………………………………………IX
LIST OF APPENDIX…………………..…………………………………….……XI
Chapter 1: Literature Review………………………………………………………….1
1.1. Current studies of breast cancer development………………………………...1
1.1.1. Epidemiology of breast cancer prevalence………………………………….1
1.1.2. Breast cancer progression…………………………………………………...1
1.2. Endogenous steroids hormones and breast cancer…………………………….2
1.2.1. Steroid hormones in normal tissue and breast cancer………………………2
1.2.2. Steroid hormones biosynthesis……………………………………………...2
1.3. Estrogen receptors in breast cancer formation…………………………..……..2
1.3.1. Estrogen receptors………………………………………………………….2
1.3.2. The role of estrogen receptors in breast cancer…………………….............3
1.4. Ca2+ and breast cancer development…………………………………………...3
1.4.1. Ca2+ in Breast cancer……………………………………………………….3
1.4.2. Extracellular Ca2+ pathway s in breast cancer……………………………...3
1.4.3. The purpose and design of this study………………………………………4
Chapter 2: Characterization of breast tumor development in 4T1-bearing mice..6
2.1. Introduction…………………………………………………………………...…6
2.1.1. The trend of breast cancer incidence in Asia women……………….………6
2.1.2. The 4T1-bearing breast cancer metastasis model………………………..…6
2.1.3. The purpose and design of this study…………………………………….…6
2.2. Material and methods…………………………………………………...……………7
2.2.1. Reagents……………………………………………………………….……7
2.2.2. Cell line and cell culture……………………………………………….……7
2.2.3. Migration assay……………………………………………………..…………....7
2.2.4. Animal care……………………………………………………………..….7
2.2.5. In vivo tumor allogeneic model……………………………………………..7
2.2.6. In vivo imaging……………………………………………………………...8
2.2.7. Data analysis and statistical evaluation……………………………….…….8
2.3. Results…………………………………………………………………………….8
2.3.1. The influences of various endogenous hormones on the migration of 4T1 breast 
      cancer cell……...…………………………………………………………..8
2.3.2. The influence of hormonal imbalance on the formation of breast cancer in premature mice…………………………………..…………………….…..8
2.3.3. The influence of age-dependent effect on tumor development in OVX mice………………………………………………………………………..9
2.3.4. The influence of prolonged exposure to DHEA on the development of breast 
      tumors……………..…………………………………………………….…9
2.3.5. Comparison of uterine estrogenicity between E2- and DHEA- treated mice……………………………….…………………………………..…9
Chapter 3: Induction of breast cancer metastasis by activated ERβ via the opening of TRPV1………………………………………..…….………………10
3.1. Introduction………………………………………………………………...…..10
3.1.1. Clinical studies of ERβ in aggressive breast cancer patients during the perimenopausal period…………………………………….………….….10
3.1.2. The role of Ca2+ in aggressive breast cancer patients during the perimenopausal period…...........................................................................10
3.1.3. The purpose and designs of this study…………………………………….10
3.2. Material and methods……………………………………………………….…11
3.2.1. Reagents and antibodies...............................................................................11
3.2.2. Cell line and cell culture...............................................................................11
3.2.3. Animal care...................................................................................................11
3.2.4. In vivo tumor allogeneic model....................................................................11
3.2.5. In vivo imaging.............................................................................................12
3.2.6. MTT assay....................................................................................................12
3.2.7. Migration assay.............................................................................................12
3.2.8. Western blot analysis....................................................................................12
3.2.9. Calcium concentration image.......................................................................13
3.2.10. Trasnfection of shRNA to 4T1……………………………………………….13
3.2.11. Data analysis and statistical evaluation......................................................13
3.3. Results……………………………………………………………………….......13
3.3.1. Expression of ERβ and TRPV1 in 4T1................................................................13
3.3.2. The induction of 4T1-containing tumor metastasis by E2 and DHEA........13
3.3.3. Activated TRPV1 causes cell migration via tumor cell morphological changes and the elevation of intracellular calcium.......................................14
3.3.4. Activated ERβ accelerates cell migration via TRPV1.................................14
3.3.5. Acceleration of tumor metastasis by activated ERβ is
     TRPV1-dependent…………………………………………..…………….15
4. Discussion…………………………………………………………………………15
4.1. Summary of this study……………………………………………………….15
4.2. Exposure to DHEA promotes breast cancer progression via ERβ…………...16
4.3. Contribution of TRPV1 in aggressive 4T1 breast cancer cells...............................16
4.4. ERβ regulate TRPV1-induced 4T1 cell migration..........................................17
4.5. Significant of this study………………………………………………………....17
Chapter 5: References………………………………………………………………18
Chapter 6: Figures ……………………....………………………………………….23
Chapter 7: Appendix……………….………………………………………………..………..51

List of figures
Figure 1. The influences of various hormones on 4T1 breast cancer cell migration..23
Figure 2. The influence of hormone imbalance on the development of breast tumors in
mice………………………………………………………………………..24
Figure 3. The influence of age-dependent effect on tumor development in OVX
 mice………………………………………………………………………..25
Figure 4. The influence experiment period on the development of breast tumors in
        mature OVX female mice……………………………………………….....26
Figure 5. The influence of E2 and DHEA on the uterus in mature OVX female mice…...27
Figure 6. Western blot was used to determine the expression of ERα, ERβ and TRPV1 in MCF-7 and 4T1 breast cancer cells……………………………………..28
Figure 7. Dose effect of ERβ activators and blocker on ce　l　l number and cell viability on
        4T1 cells………………………………………………………………..29
Figure 8. Effect of activated ERβ on cell migration……………………………...………30
Figure 9. Effect of knockdown ERβ on E2 and DHEA-induced migration………………31
Figure 10. (a) Effect of ERβ activators (E2) on the size of 4T1-containing tumor and liver 
in OVX female mice (b) Effect of ERβ activators (E2) on ERα expression at uterus tissue (c) Effect of ERβ activators (E2) on ERβ expression at tumor tissue …………………………………………………………………………..32
Figure 11. (a) Effect of ERβ activators (DHEA) on the size of 4T1-containing tumor and 
liver in OVX female mice (b) Effect of ERβ activators (E2) on ERα expression at uterus tissue (c) Effect of ERβ activators (DHEA) on ERβ expression at tumor tissue……………………………………………………………………33
Figure 12. Dose effect of TRPV1 activator and blocker on cell number and cell viability on 
4T1 cells…………………………………….…………………………………34
Figure 13. Effect of activated TRPV1 on 4T1 breast cancer cell (a) morphology (b) relative 
intracellular Ca2+ concentration (c) migration…………………..………….….35 
Figure 14. Effect of ionomycin and EGTA on 4T1 breast cancer cell (a) morphology (b) 
relative intracellular Ca2+ concentration (c) migration………………..……….36
Figure 15. Effect of Cap (TRPV1 activator) and EGTA on 4T1 breast cancer cell (a) 
morphology (b) relative intracellular Ca2+ concentration (c) migration……….37 
Figure 16. Effect of ionomycin and EGTA on cell viability on 4T1 cells…………………38
Figure 17. Effect of ionomycin and EGTA on migrated ability on 4T1 cells…………..…39
Figure 18. Effect of TRPV1 antagonist and E2 on 4T1 breast cancer cell (a) morphology
(b) relative intracellular Ca2+ concentration (c) migration…………………….40
Figure 19. Effect of TRPV1 antagonist and DHEA on 4T1 breast cancer cell (a)
morphology (b) relative intracellular Ca2+ concentration (c) migration………41
Figure 20. Effect of TRPV1 endogenous activator and DAG lipase inhibitor on 4T1 breast  
         cancer cell (a) morphology (b) relative intracellular Ca2+ concentration (c)  
         migration…………………………………………………………………...42
Figure 21. Effect of OAG and RHC80267 on cell viability on 4T1 cells…………………43
Figure 22. Effect of DAG lipase inhibitor and E2 on 4T1 breast cancer cell (a)
morphology (b) relative intracellular Ca2+ concentration (c) migration……….44
Figure 23. Effect of DAG lipase inhibitor and DHEA on 4T1 breast cancer cell (a)
morphology (b) relative intracellular Ca2+ concentration (c) migration……….45
Figure 24. (a) Effect of OAG and ERβ blocker on 4T1 breast cancer cell (a) morphology
(b) relative intracellular Ca2+ concentration (c) migration……………………46
Figure 25. (a) Effect of Cap and ERβ blocker on 4T1 breast cancer cell (a) morphology (b)
relative intracellular Ca2+ concentration (c) migration………………………47
Figure 26. Effect of knockdown ERβ on TRPV1 activators-induced migration………….48
Figure 27. (a) Effect of CapZ (TRPV1 blocker) on E2-induced tumor size increment in
OVX female mice. (b) Effect of CapZ on ERβ and TRPV1 expression at tumor
tissue…………………………………………………………………………...49
Figure 28. (a) Effect of CapZ (TRPV1 blocker) on DHEA-induced tumor size increment in 
OVX female mice. (b) Effect of CapZ on ERβ and TRPV1 expression at tumor 
tissue………………………………………………………………………...…50

LIST OF APPENDIX
Appendix 1. Steroid hormones biosynthesis in ovaries…………..…………………51
Appendix 2. Steroid hormones biosynthesis in adrenal gland……………........….52
Appendix 3. Domain organization of human ERα and ERβ.…………………...…..53
Appendix 4. STIM1-mediated Ca2+ influx regulates cell migration…….………...54
 


                                    

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