Mechanism of Fatty Acids on Fetal Origin and Antiestrogen Resistant Breast Cancer Development.

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Project title/計畫英文名

Project Number/計畫編號

NSC99-2320-B002-025-MY3

Translated Name/計畫中文名

脂肪酸對子代乳癌生成及乳癌細胞抗藥性之研究

Project Principal Investigator/計畫主持人

HUI-MIN SU

Funding Organization

National Science and Technology Council

Website

link

Start date/計畫起

01-08-2012

Expected Completion/計畫迄

12-07-2013

摘要：本研究在探討脂肪酸對子代乳癌生成及乳癌細胞抗藥性之可能作用機制。我們發現親代懷孕時期攝取高脂肪飼料，最易促進其子代乳癌生成。乳癌組織較一般乳腺組織富含10～15 倍的arachidonic acid (20：4n-6)，推論20：4n-6 在乳癌生成中扮演一重要角色。我們也發現胚胎泌乳期，藉由親代補充魚油，可有效預防抑制子代乳癌生成，然其作用機制不詳。所以我們假設乳癌發生可能源自胚胎發育時，因親代攝取高n-6 脂肪酸飼料，將促進致癌性雌激素代謝產物產生，導致雌子代成長後乳癌生成，而非子代出生後因體內雌激素影響所致。然低n-6 脂肪酸攝取或魚油補充，可抑制之。乳癌之嚴重性在於乳癌發生後，服用抗雌激素或抑制雌激素生成藥物後產生抗藥性。當抗藥性發生時會增加乳癌細胞質中雌激素受器α (estrogen receptor α, ERα)及其nongenomic signaling、cyclin D1 表現和NF-κB DNA binidng activity。我們發現docosahexaenoic acid (DHA, 22:6n-3) 可有效減少位在細胞質中的ERα表現量，抑制MAPK 訊息傳遞，降低cyclin D1 及乳癌細胞存活度。我們將進一步探討DHA 是否可藉抑制ERα作用及NF-κB 活性，而抑制抗藥性乳癌細胞生成。而20:4n-6 可促進之。本研究將有助於瞭解脂肪酸對乳癌生成及抗藥性之影響，以提供有力數據證明親代在懷孕時可藉補充魚油，預防其雌性子代成長後乳癌發生。若乳癌生成可藉補充魚油以減緩其抗藥性生成。
Abstract: The aim of this proposal is to study the mechanism of n-6 polyunsaturated fatty acids(PUFA) and n-3 PUFA on fetal origin breast cancer susceptibility and on nongenomicestrogen receptor α (ERα) signaling and nuclear factor kappaB (NF-κB) activation indrug-resistant human breast cancer cell line MCF-7.We previous found that exposure in utero to a maternal high n-6 PUFA diet duringpregnancy is more important in increasing the risk of breast cancers in the female offspringthan exposure of the offspring to the same high n-6 PUFA diet later in life. We alsodemonstrated that exposure to a high n-6 PUFA diet with n-3 PUFA supplementation duringthe perinatal period via maternal intake has a greater effect in preventing breast cancer thanthe same exposure, but with n-3 PUFA supplementation only during puberty or adulthoodlater life. However, the mechanism of n-6 and n-3 PUFA on fetal origin breast cancersusceptibility is not known.The mortality of breast cancers is due to the progressing from antiestrogen-sensitivephenotype to an antiestrogen-resistant with metastatic aggressive properties. The inhibition ofNF-κB overcomes the tamoxifen-resistance MCF-7. It is suggested that extranuclear ERαlevels, the associated nongenomic signaling, and cyclin D1 over expression causeantiestrogen resistance of breast cancers. We previous found that extranuclear ERα levels,MAPK signaling, cyclin D1 expression, and cell viability is reduced in docosahexaenoic acid(DHA, 22:6n-3)-treated MCF-7 cells. It is important to know whether DHA has the sameeffect in antiestrogen-resistant MCF-7.We propose to study, both in vivo and in vitro, to understand the mechanism of n-6 andn-3 PUFA on fetal origin breast cancer susceptibility and development of resistance to breastcancer therapy.In the in vivo study, we hypothesize that breast cancer is fetal origin that a maternal highn-6 PUFA diet mediating carcinogenic estrogen metabolism during pregnancy would result inthe risk of breast cancers in the female offspring rather than oestrogen exposure in postnatallife that rats exposed to a high n-6 PUFA diet from in utero through whole life with or withoutoestrogen deprivation in postnatal life. We study the effect of high or low n-6 PUFA diet withor without n-3 PUFA supplementation during pregnancy on estrogen metabolism. In addition,we investigate whether there is any correction among arachidonic acid levels, NF-κBactivation and tumor weight in mammary tumor.In the in vitro study, we hypothesize n-3 PUFA reduce but n-6 PUFA enhance nongenomicERα signaling and NF-κB activation in tamoxifen-resistance or long-term estrogendeprivation MCF-7. We propose NF-κB DNA-binding activity cause drug resistance of breastcancer that is overcome by DHA. We hypothesize that DHA will enhance ERα degradationand inhibit its related signaling.This study should contribute the understanding n-6 PUFA and n-3 PUFA on fetal originand antiestrogen resistant breast cancer development to determine whether DHA has potentialas a nature supplementation during pregnancy on the prevention of breast cancer in the femaleoffspring and as an alternative adjunctive endocrine therapy against the resistance ofestrogen-responsive breast cancers.

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Mechanism of Fatty Acids on Fetal Origin and Antiestrogen Resistant Breast Cancer Development.

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