Mukhopadhyay Sutapa, Mukherjee Shyamali, Das Salil K
Division of Cancer Biology, Department of Biomedical Sciences, Meharry Medical College, Nashville, TN, USA.
Glycoconj J. 2006 May;23(3-4):199-207. doi: 10.1007/s10719-006-7925-3.
Expression of peripheral benzodiazepine receptors (PBR) has been found in every tissue examined; however, it is most abundant in steroid-producing tissues. Although the primary function of PBR is the regulation of steroidogenesis, its existence in nonsteroidogenic tissues as well as in other cellular compartments including the nucleus suggests that there may be other roles for PBR. Our laboratory reported earlier a significant increase of PBR density in the nucleus of DMBA-induced malignant submandibular glands of rats, suggesting a role of PBR in nuclear events of peripheral tissues. Since then numerous studies have demonstrated the abundance of PBR in tumors. Numerous studies implicate a role for cholesterol in the mechanisms underlying cell proliferation and cancer progression. Based on studies with a battery of human breast cancer cell lines and several human tissue biopsies, Hardwick et al. suggested that PBR expression, nuclear localization, and PBR-mediated cholesterol transport into the nucleus are involved in human breast cancer cell proliferation and aggressive phenotype expression. The purpose of the present study is to confirm this hypothesis by developing an animal breast cancer model and correlating the above events with the breast cancer. Weanling rats were maintained on a diet containing animal protein (casein) for 30 days and then a single dose of DMBA in sesame oil (80 mg/kg) was administered by gavage to the animals. Control animals received the vehicle only. After 122 days of DMBA administration, the animals were sacrificed. All tumors were detected by palpation. B(max) of PBRs was 52.6% and 128.4% higher in the non-aggressive and aggressive cancer tissues, respectively, than that in normal tissues. Cholesterol uptake into isolated nuclei was found to be higher in both non-aggressive and aggressive tumor breast tissue than that in control tissue. There was also corresponding increase in B(max) of PBRs in the nucleus of cancer tissues. Furthermore, the nuclear nucleoside triphosphatase (NTPase) activity was found to be higher in aggressive tumor tissues than that in non-aggressive tumor tissues. In conclusion, these data suggest that PBR ligand binding, and PBR-mediated cholesterol transport into the nucleus may be involved in the development of mammary gland adenocarcinoma, thus participating in the advancement of the disease.
在外周苯二氮䓬受体（PBR）已在所有检测的组织中被发现；然而，它在类固醇生成组织中最为丰富。尽管PBR的主要功能是调节类固醇生成，但其在非类固醇生成组织以及包括细胞核在内的其他细胞区室中的存在表明，PBR可能还有其他作用。我们实验室较早前报道，在二甲基苯并蒽（DMBA）诱导的大鼠恶性颌下腺细胞核中，PBR密度显著增加，提示PBR在外周组织的核事件中发挥作用。从那时起，大量研究已证明肿瘤中PBR含量丰富。大量研究表明胆固醇在细胞增殖和癌症进展的潜在机制中起作用。基于对一系列人乳腺癌细胞系和多例人体组织活检的研究，哈德威克等人提出，PBR表达、核定位以及PBR介导的胆固醇转运入核与人类乳腺癌细胞增殖和侵袭性表型表达有关。本研究的目的是通过建立动物乳腺癌模型并将上述事件与乳腺癌相关联来证实这一假设。将断乳大鼠用含动物蛋白（酪蛋白）的饲料饲养30天，然后通过灌胃给动物单次注射溶于芝麻油的DMBA（80毫克/千克）。对照动物仅接受赋形剂。在给予DMBA 122天后，处死动物。所有肿瘤均通过触诊检测。在非侵袭性和侵袭性癌组织中，PBR的最大结合容量（B(max)）分别比正常组织高52.6%和128.4%。发现非侵袭性和侵袭性肿瘤乳腺组织中分离细胞核的胆固醇摄取均高于对照组织。癌组织细胞核中PBR的B(max)也相应增加。此外，发现侵袭性肿瘤组织中的核核苷三磷酸酶（NTPase）活性高于非侵袭性肿瘤组织。总之，这些数据表明，PBR配体结合以及PBR介导的胆固醇转运入核可能参与乳腺腺癌的发生发展，从而推动疾病进展。
