三陰性乳癌（triple-negative breast cancer，簡稱TNBC）是ER（雌激素受體，estrogen receptor）、PR（黃體素受體，progesterone receptor）及Her2（第二型人類上皮細胞生長因子受體，human epidermal growth factor receptor 2）均呈陰性的一種乳癌。目前臨床的治療顯示TNBC的治療頗為棘手，原因是此類型乳癌缺乏有效的治療藥物可供使用。實驗研究顯示上皮生長因子受體（epidermal growth factor receptor，EGFR）酪氨酸激?抑製劑（tyrosine kinase inhibitor，TKI）能有效地抑制TNBC細胞的增殖，但是這些TKI在臨床治療上的效果卻不甚理想，其原因可能是由腫瘤細胞和鄰近基質細胞之間的交互作用所造成。例如，腫瘤旁的纖維母細胞（fibroblast）會藉由分泌肝細胞生長因子（hepatocyte growth factor，HGF）誘導TNBC產生對TKI的抗性，顯示腫瘤的微環境（microenvironment）會影響腫瘤細胞的性質。 為了能夠有效地找尋TNBC的抑制藥物，本研究建立了一個以纖維母細胞共同培養，對乳癌細胞MDA-MB-468進行洋菜膠腫瘤形成測試的實驗系統，並在本研究中，藉以測試與篩選小巢狀麴菌（Aspergillus nidulans）之二次代謝產物對TNBC的抑制活性。結果發現小巢狀麴菌CDS1008之二次代謝產物能抑制纖維母細胞所調節乳癌細胞MDA-MB -468形成腫瘤細胞群落。進一步分離純化這些二次代謝產物，發現其中兩個主要的化合物 ─ austinol和dehydroaustinol會抑制MDA- MB- 468細胞群落的形成；而另一個二次代謝產物 ─ sterigmatocystin為已知的黴菌毒素，其對MDA- MB- 468細胞群落的形成則顯示高度的抑制作用。 本研究以纖維母細胞共同培養的方式，對乳癌細胞MDA-MB-468進行洋菜膠腫瘤形成測試，以篩選TNBC的抑制藥物，結果發現小巢狀麴菌的二次代謝產物能有效地抑制纖維母細胞所促進TNBC形成腫瘤能力。這些二次代謝產物抑制腫瘤的機制值得進一步研究探討。 Triple-negative breast cancer (estrogen receptor-, progesterone receptor- and Her2-negative breast cancer; TNBC) is an aggressive histological subtype of breast cancer with limited choice of treatments. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been shown to inhibit proliferation of TBNCs efficiently, however, these TKIs lacked efficacy in clinical treatment. This may be caused by cross-talk between cancer cells and neighboring stromal cells. For example, hepatocyte growth factor (HGF) secreted by cancer-associated fibroblasts has been shown to induce TKI resistance of TNBCs, indicating that microenvironment affected properties of cancer cells. To survey the effective TNBC inhibitors, we established a soft agar colony formation system for breast cancer MDA-MB-468 cells, in which fibroblasts were co-cultured. In this study, we test secondary metabolites of Aspergillus nidulans for their inhibitory activities on TNBCs by using this system. We found that secondary metabolites of Aspergillus nidulans inhibited fibroblast-mediated colony formation of MDA-MB-468 cells. Further study showed that two major meroterpenoid components, austinol and dehydroaustinol, possessed inhibitory activities on MDA-MB-468 cell colony formation, compared to a mycotoxin component, sterigmatocystin, which exhibited a highly inhibitory effect. We established a breast cancer colony formation system with co-culture of fibroblasts to survey the TNBC inhibitors. The mechanisms that the metabolites inhibited TNBC colony formation efficiently will be further characterized.
