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The Relationship between the Mouse Mammary Tumor Virus-Like Sequences and the Expression of Hormonal Receptors, HER2, and PTEN in Canine and Feline Mammary Tumors
|摘要:||截至目前已有許多環境危險因子被認為和人類乳癌的發生有關，其中包括老鼠乳腺腫瘤病毒(mouse mammary tumor virus, MMTV)亦被提出與人類乳癌的發生有關聯。MMTV 為致癌B 型反轉錄病毒，除能誘導小鼠乳癌形成之外，也可在人及犬細胞中進行複製，於人類乳癌中高度表現類似老鼠乳腺腫瘤之病毒序列，且初代培養之人類乳癌細胞可製造出類似老鼠乳腺腫瘤病毒之病毒顆粒。經調查發現乳癌病患飼養犬當寵物的比例是年紀相符的對照控制組的兩倍。另有一假說推論犬或許是MMTV 傳播至人類的媒介。而我們已於108 隻犬與11 隻貓之乳腺腫瘤組織中，偵測到MMTV-like env 與LTR基因序列；結果顯示在犬惡性乳腺腫瘤中的出現比例分別為3.49%及18.6%，且經比對後MMTV-like LTR 基因序列與MMTV 的基因相似度為89%。在貓惡性乳腺腫瘤中出現的比例分別為22.2%及22.2%，基因序列相似度為94%至98 %。再者，phosphatase andtensin homolog (PTEN)為一抑腫瘤基因，為AKT/PKB 之負調控因子，於人和犬乳癌組織中PTEN 的低表現或是不表現與癌症的惡性表徵有一正相關性。Wnt 路徑的異常活化也被證實為MMTV 的一種致腫瘤機轉，且PTEN 的缺損會加速由MMTV-Wnt 轉殖小鼠之乳癌發生。就我們所知，目前尚無研究指出犬乳癌組織中是否有老鼠乳腺腫瘤病毒或類似老鼠乳腺腫瘤病毒序列的出現。本研究除利用nested PCR 技術持續監測犬貓乳腺腫瘤中之MMTV-like env 與LTR 序到外，並擴大樣本來源如人和小鼠。另外也將聯結該序列的出現和臨床及病理表現(如腫瘤組織學分級、荷爾蒙受體、HER2、PTEN 及pAKT等表現)之間的關聯，並分析其預後。最後探討犬隻是否可能是傳染人乳癌的因子的可能性。|
Several environmental risk factors have been proposed for human sporadic breast cancerincluding mouse mammary tumor virus (MMTV) which is an oncogenic B retrovirusinducing breast cancer in mice and could productively replicate also in canine and humancells. There are many reports from different groups identifying MMTV-like sequences thatare highly expressed in human breast cancer. The primary human breast cancer cultures alsoproduced viral particles that are similar to the MMTV. Moreover, there is a significantlyincreased frequency of dog owners among female patients with breast cancer as compared toan age matched group of the female population. Moreover, there is a hypothesis that the dogscould transmit MMTV or a MMTV-like virus to human after they themselves had acquiredthe infection. In our study from 108 canine and 11 feline mammary gland tumors, thespecific MMTV-like env and LTR sequences had been detected in 3.49% of and 18.6% ofdogs with malignant mammary tumors, respectively. When MMTV-like LTR sequences inour study were aligned with those of MMTV identified from mouse, 89% similarity wasfound. The specific MMTV-like env and LTR sequences had also been detected in 22.2% ofand 22.2% of feline malignant mammary tumors, respectively. In comparison with theidentity of these sequences in our study and MMTV identified from NIH 3T3(MMTV-positive murine cell line) and MMTV-like sequences, results showed the identityranging from 94% to 98%. Nevertheless, phosphatase and tensin homolog (PTEN) is atumor-suppressor gene that could negatively regulate the AKT/PKB. In human and caninemammary cancers, decreased-expression or non-expression of PTEN had a positive relationto malignancy of cancers. In addition, the abnormally activated Wnt signaling wasdemonstrated that is one of the tumor-forming mechanisms of MMTV. The deficiency ofPTEN accelerates mammary tumorigenesis in MMTV-Wnt transgenic mice. To ourknowledge, MMTV or MMTV-like sequences have not been investigated in caninemammary carcinomas. In this study, we will continue the research related to the detection ofMMTV-like env and LTR sequences in canine and feline mammary tumors by nested PCRtechnique, and extend the spectrum of sample source to include mammary tumors from thehuman and mouse. Further, the relationship between the detection of MMTV-like env andLRT sequences in canine and feline mammary tumors and clinicopathologic findings (i.e.,histologic grade, the expression of hormonal receptors, HER2, PTEN, and pAKT) will beanalyzed and explored. And the possibilities whether dogs could transmit MMTV or aMMTV-like virus after they themselves had acquired the infection will also be identified.
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