Rochefort H, Glondu M, Sahla M E, Platet N, Garcia M
Molecular and Cellular Endocrinology of Cancer, INSERM Unit 540 and Montpelier University, 60 rue de Navacelles, 34090 Montpelier, France.
Endocr Relat Cancer. 2003 Jun;10(2):261-6. doi: 10.1677/erc.0.0100261.
Estrogen receptor (ER)-positive breast cancers generally have a better prognosis and are often responsive to anti-estrogen therapy, which is the first example of a successful therapy targeted on a specific protein, the ER. Unfortunately ER-negative breast cancers are more aggressive and unresponsive to anti-estrogens. Other targeted therapies are thus urgently needed, based on breast cancer oncogene inhibition or suppressor gene activation as far as molecular studies have demonstrated the alteration of expression, or structure of these genes in human breast cancer. Using the MDA-MB.231 human breast cancer cell line as a model of ER-negative breast cancers, we are investigating two of these approaches in our laboratory. Our first approach was to transfect the ER or various ER-deleted variants into an ER-negative cell line in an attempt to recover anti-estrogen responsiveness. The unliganded receptor, and surprisingly estradiol, were both found to inhibit tumor growth and invasiveness in vitro and in vivo. The mechanisms of these inhibitions in ER-negative cancer cells are being studied, in an attempt to target the ER sequence responsible for such inhibition in these cancer cells. Another strategy is trying to inhibit the activity or expression of an oncogene specifically overexpressed in most breast cancers. This approach was recently shown by others to be efficient in breast cancer therapy with HER2-Neu oncogene amplification using Herceptin. Without excluding other molecular putative targets, we have focused our research on cathepsin D as a potential target, since it is often overexpressed in aggressive human breast cancers, including ER-negative tumors, and rarely associated with HER2-Neu amplification. Our first results obtained in vitro on cell lines and in vivo in tumor xenografts in nude mice, illustrate that the mode of action of cathepsin D in breast cancer is useful to guide the development of these therapies. In the past 20 years we have learned that the action of cathepsin D is complex and involves both intracellular and extracellular activities due to its proteolytic activity and to interactions with membrane components without catalytic activity. Each of these mechanisms could be potentially inhibited in an attempt to prevent tumor growth. Breast cancer is a very heterogeneous and multigenic disease and different targeted therapies adapted to each category of breast cancer are therefore required. Validated assays in the primary tumor of molecular markers such as ER, HER2-Neu and cathepsin D should help to predict which targeted therapy should be applied to cure breast cancer patients.
雌激素受体（ER）阳性乳腺癌通常预后较好，且往往对抗雌激素治疗有反应，这是针对特定蛋白质（即ER）的成功治疗的首个实例。不幸的是，ER阴性乳腺癌更具侵袭性，对抗雌激素无反应。因此，基于乳腺癌致癌基因抑制或抑癌基因激活，迫切需要其他靶向治疗，因为分子研究已证明这些基因在人类乳腺癌中的表达或结构发生了改变。以MDA-MB.231人乳腺癌细胞系作为ER阴性乳腺癌的模型，我们正在实验室研究其中两种方法。我们的第一种方法是将ER或各种ER缺失变体转染到ER阴性细胞系中，试图恢复抗雌激素反应性。未结合配体的受体，令人惊讶的是雌二醇，在体外和体内均被发现可抑制肿瘤生长和侵袭性。目前正在研究这些在ER阴性癌细胞中的抑制机制，试图靶向这些癌细胞中负责这种抑制作用的ER序列。另一种策略是尝试抑制在大多数乳腺癌中特异性过表达的致癌基因的活性或表达。最近其他人表明，这种方法在使用赫赛汀治疗HER2-Neu致癌基因扩增的乳腺癌中有效。在不排除其他分子假定靶点的情况下，我们将研究重点放在组织蛋白酶D作为潜在靶点上，因为它在侵袭性人类乳腺癌（包括ER阴性肿瘤）中经常过表达，且很少与HER2-Neu扩增相关。我们在体外细胞系和裸鼠肿瘤异种移植体内获得的初步结果表明，组织蛋白酶D在乳腺癌中的作用模式有助于指导这些治疗方法的开发。在过去20年中我们了解到，组织蛋白酶D的作用很复杂，由于其蛋白水解活性以及与无催化活性的膜成分的相互作用，其作用涉及细胞内和细胞外活性。为了阻止肿瘤生长，这些机制中的每一种都可能被潜在抑制。乳腺癌是一种非常异质性和多基因的疾病，因此需要针对每类乳腺癌的不同靶向治疗。对分子标志物如ER、HER2-Neu和组织蛋白酶D在原发性肿瘤中的验证检测应有助于预测应采用哪种靶向治疗来治愈乳腺癌患者。
