在上月蒙特利爾舉行的年度國際乳腺癌研究協(xié)會(huì)報(bào)告大會(huì)（International Association for Breast Cancer Research）上,，加州大學(xué)戴維斯分校（UC Davis）研究人員宣布近期研究總結(jié)得到的一項(xiàng)假說：管內(nèi)原位癌(ductal carcinoma in situ，DCIS)和侵犯性乳癌細(xì)胞(invasive breast cancer,，IBC)有可能來自相同的乳腺癌祖細(xì)胞,。
“這些研究的意義在于，乳腺癌遺傳密碼早在癌癥前期階段即已確定,，” UC Davis比較醫(yī)學(xué)中心（Center for Comparative Medicine）突變小鼠病理學(xué)實(shí)驗(yàn)室主任,、病理學(xué)教授Robert D. Cardiff說，“研究結(jié)果對(duì)預(yù)防和治療乳腺癌研究影響深遠(yuǎn)。”
傳統(tǒng)觀點(diǎn)認(rèn)為DCIS作為常見的一種局部乳腺癌（localized breast cancer）,，只有在有附加遺傳變異時(shí)才會(huì)通過乳腺擴(kuò)散,。新假說認(rèn)為乳腺癌祖細(xì)胞在癌前期病變(precancerous lesions)即已存在，遺傳程序早已確定發(fā)育為DCIS以至IBC的命運(yùn),。
UC Davis模仿人類DCIS,，利用基因工程技術(shù)得到乳腺上皮內(nèi)瘤（mammary intraepithelial neoplasia，MIN）小鼠模型,。目前這種小鼠模型只能從UC Davis獲取,。國際乳腺癌研究協(xié)會(huì)報(bào)告大會(huì)即將離任會(huì)長Cardiff將假說整理為文章“Mammary Precancers: Old Concept and New Biology”。他說：“此假說提示,，我們一直以來的乳腺癌靶標(biāo)細(xì)胞都是錯(cuò)誤的,，我們需要建立一種能夠在乳腺癌高發(fā)婦女中檢測(cè)乳腺癌祖細(xì)胞并在其癌變前將其消滅的方法。”
以下是四支UC Davis研究隊(duì)伍在蒙特利爾大會(huì)上所作的關(guān)于小鼠MIN,、DCIS和侵犯性乳癌細(xì)胞的研究報(bào)告,。
UC Davis癌癥研究中心生化和分子醫(yī)學(xué)副教授Kermit L Carraway III帶領(lǐng)的研究小組報(bào)告內(nèi)容為Nrdp1在癌變途徑中的作用。他們發(fā)現(xiàn),，當(dāng)人類和小鼠乳腺細(xì)胞Nrdp1表達(dá)過量時(shí),，一種能夠抑制癌細(xì)胞生長、擴(kuò)散的叫做ErbB3的生長因子水平下降,。相同現(xiàn)象發(fā)生于過表達(dá)ErbB2的乳腺癌細(xì)胞,。與小鼠生長因子ErbB2相對(duì)的人類生長因子為HER2，有研究顯示HER2在1/4人類乳腺癌細(xì)胞中都存在,。Carraway III等的研究結(jié)果提示,，Nrdp1也許是治療HER2陽性人類乳腺癌的潛在靶標(biāo)。
第二支研究小組報(bào)告說,，可以在幾個(gè)環(huán)節(jié)上制止MIN細(xì)胞向乳腺癌轉(zhuǎn)化,。由比較醫(yī)學(xué)中心高級(jí)研究員Lawrence Young和病理學(xué)副教授Jeff Gregg率領(lǐng)的研究小組發(fā)現(xiàn)：能夠快速誘導(dǎo)細(xì)胞凋亡的抗生素雷帕霉素(rapamycin)，對(duì)某些種類MIN細(xì)胞無效,。研究小組下一步打算利用基因芯片分析這些在雷帕霉素作用后仍能存活的癌癥細(xì)胞,，希望找到關(guān)鍵基因，預(yù)計(jì)此基因?qū)⒊蔀樗幬镅邪l(fā)的候選靶標(biāo),。
第三支小組報(bào)告指出,，利尿劑（diuretics）也許能夠用于治療DCIS。生理學(xué),、膜生物學(xué)副研究員Steven Anderson和Peter Cala利用成像分析技術(shù)發(fā)現(xiàn),，MIN細(xì)胞存活需要一種能夠維持乳腺微環(huán)境有利pH的分子（sodium/hydrogen exchanger）。Diuretics抑制sodium/hydrogen 轉(zhuǎn)化,，導(dǎo)致微環(huán)境pH偏酸性,，能夠殺死癌細(xì)胞。
第四支研究小組報(bào)告，其獲得一種能夠檢測(cè)乳腺癌癌變關(guān)鍵基因的新方法,。UC Davis 比較醫(yī)學(xué)中心研究員Patrizia Damonte和生理學(xué)副教授Alexander Borowsky率領(lǐng)的研究小組,，分離MIN癌變組織為單個(gè)細(xì)胞，然后培養(yǎng)單個(gè)細(xì)胞為多細(xì)胞團(tuán),，尋找能夠發(fā)生癌變的細(xì)胞團(tuán),。此研究小組目前正在尋找癌變遺傳機(jī)制。
英文原文：
Breast Cancer Findings Suggest New Ways To Detect And Destroy Cells Before They Become Cancerous
New UC Davis research supports the recent hypothesis that both ductal carcinoma in situ and invasive breast cancer develop from the same breast cancer progenitor cells. The research was reported at the annual meeting of the International Association for Breast Cancer Research in Montreal last month.
"The implication of these studies and others is that the genetic code for breast cancer is probably written at the pre-cancerous stage, so the rest is predestined," said Robert D. Cardiff, professor of pathology and director of the Mutant Mouse Pathology Lab at the UC Davis Center for Comparative Medicine. "This has profound implications for the prevention and treatment of breast cancer."
The conventional belief has been that DCIS, the most common form of localized breast cancer, spreads beyond the milk duct only if the DCIS cells are subjected to additional genetic damage. The newer hypothesis argues that breast cancer progenitor cells are present from the beginning in precancerous lesions, and are genetically programmed to progress not only to DCIS but also right on through to invasive breast cancer.
The UC Davis findings are based on studies in a line of transgenic mice engineered to develop mammary intraepithelial neoplasia, or MIN, the mouse equivalent of human DCIS.
The mouse model, developed by researchers at UC Davis and UC San Diego, is available only at UC Davis.
Cardiff, outgoing president of the International Association for Breast Cancer Research, summarized evidence for the new hypothesis in a presentation titled "Mammary Precancers: Old Concept and New Biology."
"The new hypothesis suggests that we are treating the wrong breast cancer cells," Cardiff said. "We need to determine how to correctly identify breast cancer progenitor cells in high-risk women and destroy these cells before they can become malignant."
At the Montreal meeting, four groups of UC Davis researchers reported on their work in MIN, DCIS and invasive mammary cancer in mice.
Kermit L Carraway III, an associate professor of biochemistry and molecular medicine at UC Davis Cancer Center, reported his research into the role of a substance known as Nrdp1 in the path toward malignancy. Carraway's team discovered that when mouse and human breast cancer cells have excess Nrdp1, the levels of a growth factor known as ErbB3 drop, inhibiting the cancer cells' growth and motility. The same happens in mouse breast cancer cells with excess ErbB2. The growth factor ErbB2 is the mouse counterpart of the human growth factor HER2, which is implicated in a quarter of human breast cancers. The findings suggest Nrdp1 may have a role in the treatment of HER2-positive human breast cancers.
A second team reported that the seemingly inexorable progression of MIN cells towards mammary cancer could be halted in some cases. The team, led by Lawrence Young, a senior research associate in the Center for Comparative Medicine, and Jeff Gregg, an associate professor of pathology, found that the antibiotic rapamycin quickly induced apoptosis, or rapid cell death, in some but not all MIN cell lines. The researchers' next step will be to use micro-array genetic analysis to determine which genes were expressed in the surviving malignant cells. Such genes could be promising targets for drug development.
A third team presented work suggesting that diuretics may have therapeutic potential in DCIS. Steven Anderson, an associate researcher in physiology and membrane biology, and Peter Cala, professor and chair of physiology and membrane biology, have conducted specializing imaging studies to demonstrate that MIN cells rely on a molecule known as the sodium/hydrogen exchanger to maintain a favorable pH balance within the milk ducts. Diuretics inhibit sodium/hydrogen exchange, resulting in an acidic micro-environment that is lethal to cancer cells.
"This study has potential to provide innovative new treatments for high-risk women with DCIS," Cala said. A fourth team reported on a novel method of determining which genes confer malignancy in breast cancer. Patrizia Damonte, a researcher in the UC Davis Center for Comparative Medicine, and Alexander Borowsky, an assistant professor of pathology, have separated MIN lesions into individual cells, cultured each cell into a multicellular clump and observed each clump to see which developed into cancer. They're now analyzing the genetic makeup of the malignant clumps.
