Establishing the role of Secreted-Frizzled-Related Protein (SFRP1) in metastasis formation in canine patients with mammary tumours

乳腺肿瘤是母犬最常见的肿瘤。大约50%的完好无损的母犬会患上乳腺肿瘤，其中一半会是恶性的，通常会通过转移而导致死亡。目前还没有标准化的诊断或预后分子生物标记物来指导狗的治疗。此外，乳腺癌的治疗选择大多限于手术切除病变的腺体(S)，因为化疗没有证实的生存益处，也没有靶向治疗可用。因此，临床上迫切需要一种可靠的预后生物标记物来指导治疗，并需要新的有效的治疗方案。我们最近发现分泌型卷曲相关蛋白1(SFRP1)是一种潜在的肿瘤进展风险的生物标志物。在犬乳腺肿瘤(CMT)的两个数据集中，SFRP1与转移行为增加的风险呈负相关。由于SFRP1是几个与癌症相关的促进生长途径的拮抗剂，包括典型的和非典型的Wnt-和RANK-途径，使用一种可以模拟其活性的药物治疗可能在未来开辟新的靶向治疗选择。该项目旨在将SFRP1确立为可靠的预后生物标志物，以帮助CMT的诊断，并研究由于SFRP1缺失导致CMT进展行为的生物学基础，从而确定潜在的新方法来抑制CMT的生长和进展。

Mammary tumours are the prevalent neoplasms in female dogs. ~50% of all intact bitches will develop mammary tumours of which half will be malignant, often leading to death through metastasis formation. There are currently no standardised diagnostic or prognostic molecular biomarkers available to guide treatment in dogs. Further, treatment options for mammary carcinomas are mostly limited to surgical removal of the diseased gland(s) as chemotherapy has no proven survival benefit and targeted therapies are not available. There is hence an urgent clinical need for a reliable prognostic biomarker that can guide treatment, and for new effective treatment options. We recently identified secreted frizzled-related protein 1 (SFRP1) as a potential biomarker for risk of tumour progression. SFRP1 was negatively associated with increased risk of metastatic behaviour in two datasets of canine mammary tumours (CMT). As SFRP1 is an antagonist to several cancer associated growth-promoting pathways, including the canonical and non-canonical Wnt- and RANK- pathways, treatment with a drug that could mimic its activity could potentially open up new targeted treatment options in the future. This project aims to firmly establish SFRP1 as a reliable prognostic biomarker to aid in CMT diagnostics, as well as to study the biology underlying the progressive behaviour of CMT due to SFRP1 loss, and thereby identify potential new ways to supress CMT growth and progression.