在上月蒙特利尔举行的年度国际乳腺癌研究协会报告大会（International Association for Breast Cancer Research）上，加州大学戴维斯分校（UC Davis）研究人员宣布近期研究总结得到的一项假说：管内原位癌(ductal carcinoma in situ，DCIS)和侵犯性乳癌细胞(invasive breast cancer，IBC)有可能来自相同的乳腺癌祖细胞。
“这些研究的意义在于，乳腺癌遗传密码早在癌症前期阶段即已确定，” UC Davis比较医学中心（Center for Comparative Medicine）突变小鼠病理学实验室主任、病理学教授Robert D. Cardiff说，“研究结果对预防和治疗乳腺癌研究影响深远。”
传统观点认为DCIS作为常见的一种局部乳腺癌（localized breast cancer），只有在有附加遗传变异时才会通过乳腺扩散。新假说认为乳腺癌祖细胞在癌前期病变(precancerous lesions)即已存在，遗传程序早已确定发育为DCIS以至IBC的命运。
UC Davis模仿人类DCIS，利用基因工程技术得到乳腺上皮内瘤（mammary intraepithelial neoplasia，MIN）小鼠模型。目前这种小鼠模型只能从UC Davis获取。国际乳腺癌研究协会报告大会即将离任会长Cardiff将假说整理为文章“Mammary Precancers: Old Concept and New Biology”。他说：“此假说提示，我们一直以来的乳腺癌靶标细胞都是错误的，我们需要建立一种能够在乳腺癌高发妇女中检测乳腺癌祖细胞并在其癌变前将其消灭的方法。”
以下是四支UC Davis研究队伍在蒙特利尔大会上所作的关于小鼠MIN、DCIS和侵犯性乳癌细胞的研究报告。
UC Davis癌症研究中心生化和分子医学副教授Kermit L Carraway III带领的研究小组报告内容为Nrdp1在癌变途径中的作用。他们发现，当人类和小鼠乳腺细胞Nrdp1表达过量时，一种能够抑制癌细胞生长、扩散的叫做ErbB3的生长因子水平下降。相同现象发生于过表达ErbB2的乳腺癌细胞。与小鼠生长因子ErbB2相对的人类生长因子为HER2，有研究显示HER2在1/4人类乳腺癌细胞中都存在。Carraway III等的研究结果提示，Nrdp1也许是治疗HER2阳性人类乳腺癌的潜在靶标。
第二支研究小组报告说，可以在几个环节上制止MIN细胞向乳腺癌转化。由比较医学中心高级研究员Lawrence Young和病理学副教授Jeff Gregg率领的研究小组发现：能够快速诱导细胞凋亡的抗生素雷帕霉素(rapamycin)，对某些种类MIN细胞无效。研究小组下一步打算利用基因芯片分析这些在雷帕霉素作用后仍能存活的癌症细胞，希望找到关键基因，预计此基因将成为药物研发的候选靶标。
第三支小组报告指出，利尿剂（diuretics）也许能够用于治疗DCIS。生理学、膜生物学副研究员Steven Anderson和Peter Cala利用成像分析技术发现，MIN细胞存活需要一种能够维持乳腺微环境有利pH的分子（sodium/hydrogen exchanger）。Diuretics抑制sodium/hydrogen 转化，导致微环境pH偏酸性，能够杀死癌细胞。
第四支研究小组报告，其获得一种能够检测乳腺癌癌变关键基因的新方法。UC Davis 比较医学中心研究员Patrizia Damonte和生理学副教授Alexander Borowsky率领的研究小组，分离MIN癌变组织为单个细胞，然后培养单个细胞为多细胞团，寻找能够发生癌变的细胞团。此研究小组目前正在寻找癌变遗传机制。
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.
