在上月蒙特婁舉行的年度國際乳腺癌研究協會報告大會（International Association for Breast Cancer Research）上，加州大學戴維斯分校（UC Davis）研究人員宣布近期研究總結得到的一項假說：管內原位癌(ductal carcinoma in situ，DCIS)和侵犯性乳癌細胞(invasive breast cancer，IBC)有可能來自相同的乳腺癌祖細胞。
「這些研究的意義在於，乳腺癌遺傳密碼早在癌症前期階段即已確定，」 UC Davis比較醫學中心（Center for Comparative Medicine）突變小鼠病理學實驗室主任、病理學教授Robert D. Cardiff說，「研究結果對預防和治療乳腺癌研究影響深遠。」
傳統觀點認為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才會通過乳腺擴散。新假說認為乳腺癌祖細胞在癌前期病變(precancerous lesions)即已存在，遺傳程序早已確定發育為DCIS以至IBC的命運。
UC Davis模仿人類DCIS，利用基因工程技術得到乳腺上皮內瘤（mammary intraepithelial neoplasia，MIN）小鼠模型。目前這種小鼠模型只能從UC Davis獲取。國際乳腺癌研究協會報告大會即將離任會長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細胞都是錯誤的，我們需要建立一種能夠在乳腺癌高發婦女中檢測乳腺癌祖細胞並在其癌變前將其消滅的方法。」
以下是四支UC Davis研究隊伍在蒙特婁大會上所作的關於小鼠MIN、DCIS和侵犯性乳癌細胞的研究報告。
UC Davis癌症研究中心生化和分子醫學副教授Kermit L Carraway III帶領的研究小組報告內容為Nrdp1在癌變途徑中的作用。他們發現，當人類和小鼠乳腺細胞Nrdp1表達過量時，一種能夠抑制癌細胞生長、擴散的叫做ErbB3的生長因子水平下降。相同現象發生於過表達ErbB2的乳腺癌細胞。與小鼠生長因子ErbB2相對的人類生長因子為HER2，有研究顯示HER2在1/4人類乳腺癌細胞中都存在。Carraway III等的研究結果提示，Nrdp1也許是治療HER2陽性人類乳腺癌的潛在靶標。
第二支研究小組報告說，可以在幾個環節上制止MIN細胞向乳腺癌轉化。由比較醫學中心高級研究員Lawrence Young和病理學副教授Jeff Gregg率領的研究小組發現：能夠快速誘導細胞凋亡的抗生素雷帕黴素(rapamycin)，對某些種類MIN細胞無效。研究小組下一步打算利用基因晶片分析這些在雷帕黴素作用後仍能存活的癌症細胞，希望找到關鍵基因，預計此基因將成為藥物研發的候選靶標。
第三支小組報告指出，利尿劑（diuretics）也許能夠用於治療DCIS。生理學、膜生物學副研究員Steven Anderson和Peter Cala利用成像分析技術發現，MIN細胞存活需要一種能夠維持乳腺微環境有利pH的分子（sodium/hydrogen exchanger）。Diuretics抑制sodium/hydrogen 轉化，導致微環境pH偏酸性，能夠殺死癌細胞。
第四支研究小組報告，其獲得一種能夠檢測乳腺癌癌變關鍵基因的新方法。UC Davis 比較醫學中心研究員Patrizia Damonte和生理學副教授Alexander Borowsky率領的研究小組，分離MIN癌變組織為單個細胞，然後培養單個細胞為多細胞團，尋找能夠發生癌變的細胞團。此研究小組目前正在尋找癌變遺傳機制。
"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.