Rao N A S, van Wolferen M E, Gracanin A, Bhatti S F M, Krol M, Holstege F C, Mol J A
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, The Netherlands.
J Physiol Pharmacol. 2009 May;60 Suppl 1:73-84.
Spontaneous mammary tumors are the most prevalent type of neoplasms in women as well as in female dogs. Although ovarian hormones estrogen and progesterone are known to play a key role in mammary tumorigenesis, conflicting reports have been obtained from in vivo and in vitro studies concerning the role of especially progesterone in mammary tumorigenesis. Prolonged exposure to high concentrations of progesterone during the unusually long luteal phase of the estrous cycle is suspected to be the key event in canine mammary tumorigenesis. Accordingly, previous studies have shown the development of mammary hyperplasia in dogs upon prolonged progestin administration. In this study, a dog-specific cDNA microarray was used to identify oncogenic determinants in progestin-induced canine hyperplasia (CMH) and spontaneous mammary tumors (CMC) by comparing expression profiles to those obtained from mammary glands of healthy dogs. The CMH profile showed elevated expression of genes involved in cell proliferation such as PCNA, NPY, RAN and also alterations in expression of transcription factors and cell adhesion molecules. Whereas in CMC, major alterations to the expression of genes involved in cell motility, cytoskeletal organization and extra cellular matrix production was evident besides differential expression of cell proliferation inducing genes. The overall gene expression profile of CMH was related to cell proliferation where as that of CMC was associated with both cell proliferation as well as neoplastic transformation. In conclusion, our findings support a strong cell proliferation inducing potential of progestins in the canine mammary gland. Moreover, deregulated genes identified in CMC are potentially involved in their malignant and may serve as prospective therapeutic targets.
自发性乳腺肿瘤是女性和雌性犬类中最常见的肿瘤类型。尽管已知卵巢激素雌激素和孕酮在乳腺肿瘤发生中起关键作用，但关于特别是孕酮在乳腺肿瘤发生中的作用，体内和体外研究得出了相互矛盾的报告。发情周期中异常长的黄体期期间长时间暴露于高浓度孕酮被怀疑是犬类乳腺肿瘤发生的关键事件。因此，先前的研究表明，长期给予孕激素会导致犬类乳腺增生。在本研究中，通过将表达谱与健康犬乳腺组织的表达谱进行比较，使用犬特异性cDNA微阵列来鉴定孕激素诱导的犬乳腺增生（CMH）和自发性乳腺肿瘤（CMC）中的致癌决定因素。CMH谱显示参与细胞增殖的基因如PCNA、NPY、RAN的表达升高，以及转录因子和细胞粘附分子的表达改变。而在CMC中，除了诱导细胞增殖的基因的差异表达外，参与细胞运动、细胞骨架组织和细胞外基质产生的基因表达也有明显改变。CMH的整体基因表达谱与细胞增殖有关，而CMC的基因表达谱与细胞增殖以及肿瘤转化都有关。总之，我们的研究结果支持孕激素在犬乳腺中有很强的诱导细胞增殖的潜力。此外，在CMC中鉴定出的失调基因可能参与其恶性转化，可作为潜在的治疗靶点。
