Mercier Isabelle, Bryant Kelly G, Sotgia Federica, Bonuccelli Gloria, Witkiewicz Agnieszka K, Dasgupta Abhijit, Jasmin Jean-François, Pestell Richard G, Lisanti Michael P
Kimmel Cancer Center, Department of Cancer Biology and Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Cell Cycle. 2009 May 1;8(9):1396-401. doi: 10.4161/cc.8.9.8307. Epub 2009 May 26.
Caveolin-1 (Cav-1) mutations, such as P132L, are associated with ER-positive human breast cancers. However, no immunohistochemical methods have yet been described to predict the presence of Cav-1 mutations in human breast cancer. Since the P132L mutation acts in a dominant-negative fashion and causes the mis-localization of Cav-1 in cultured cells in vitro, we hypothesized that of patients carrying this mutation would show a similar Cav-1 staining pattern in vivo. Indeed, while performing histological analysis of Cav-1 immunostaining on human breast cancer samples, we noted the emergence of two distinct epithelial staining patterns: (1) punctate peri-nuclear "Golgi-like" localization; or (2) diffuse cytoplasmic staining. The punctate peri-nuclear staining pattern was associated with ER-alpha positivity and was present mainly in well-differentiated samples. In striking contrast, the diffuse staining pattern was present in poorly differentiated samples, and was not associated with ER-status. DNA sequence analysis revealed that only well-differentiated samples with a punctate staining pattern harbored the Cav-1 P132L mutation. Thus, immunostaining of Cav-1 can be used as a first step to stratify human breast cancer patients and to predict the presence of Cav-1 mutations. As such, the punctate Cav-1 immunostaining pattern can now be used as a screening tool to select patients for Cav-1 mutational analysis.
小窝蛋白-1（Cav-1）突变，如P132L，与雌激素受体（ER）阳性的人类乳腺癌相关。然而，尚未有免疫组织化学方法可用于预测人类乳腺癌中Cav-1突变的存在。由于P132L突变以显性负性方式起作用，并导致体外培养细胞中Cav-1的定位错误，我们推测携带这种突变的患者在体内会表现出类似的Cav-1染色模式。事实上，在对人类乳腺癌样本进行Cav-1免疫染色的组织学分析时，我们注意到出现了两种不同的上皮染色模式：（1）点状核周“高尔基体样”定位；或（2）弥漫性细胞质染色。点状核周染色模式与ER-α阳性相关，主要存在于高分化样本中。与之形成鲜明对比的是，弥漫性染色模式存在于低分化样本中，且与ER状态无关。DNA序列分析显示，只有具有点状染色模式高分化样本携带Cav-1 P132L突变。因此，Cav-1免疫染色可作为对人类乳腺癌患者进行分层并预测Cav-1突变存在的第一步。据此，点状Cav-1免疫染色模式现在可作为一种筛选工具，用于选择进行Cav-1突变分析的患者。
