ABSTRACT
Objective: To assess the expression of retinoic acid receptor beta 2 (RAR-β2) in breast tumor and to evaluate the relationship between RAR-β2 expression and tumorigenesis of breast cancer. Methods: Immu-nohistochemistry was used to detect the expression of RAR-β2 protein in specimens from 40 cases of breast cancer, 40 cases of atypical ductal hyperplasia, 40 cases of fibroadenoma and 20 cases of normal breast tissues. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the mRNA expression levels of RAR-β2 gene in 20 cases of breast cancer, 20 cases of atypical ductal hyperplasia, 20 cases of fibroadenoma, and 20 cases of normal breast tissues. Results: Immunohistochemical staining results revealed that the positive expression of RAR-β2 protein showed nuclear staining. The positive expression rate of RAR-β2 was 30% (12/40) in breast cancer, 17.5% (7/40) in atypical ductal hyperplasia, 87.5% (35/40)in fibroadenoma, and 95% (19/20) in normal breast tissues. The expression of RAR-β2 protein in breast cancer was significantly lower than that in normal breast tissues (X~2=26.30, P<0.001). The expression of RAR-β2 was not significantly different between atypical ductal hyperplasia and breast cancer (P>0.05). No correlation was found between the expression of RAR-β 2 protein and the tumor size, menopausal age, lymph node metastasis, clinical stage, histological grade, or protein expression of ER and PR in breast cancer tissues (P>0.05). Follow-up results showed that 3 out of 28 patients with negative RAR-β2 expression had visceral organ metastasis, but only one of the 12 RAR-β2 positive patients had osseous metastasis. RT-PCR analysis showed that the positive expression rate of RAR-β2 mRNA in breast cancer, atypical ductal hyperplasia, fibroadenoma and normal breast tissues was 25% (5/20), 35% (7/20), 85% (17/20) and 100% (20/20), respectively. The RAR-β2 mRNA expression rate in breast cancer was significantly lower than that in normal breast tissues (X~2=30.43, P<0.001). No significant difference in RAR-β2 mRNA expression was found between atypical ductal hyperplasia and breast cancer tissues (P>0.05). Conclusion: RAR-β2 gene may play a repressive role in the initiation of breast cancer, and the loss of the expression of RAR-β2 gene may be the initial step in breast carcinogenesis.
ABSTRACT
Epidermal growth factor receptor kinase and the related human epidermal growth factor receptor-2 (HER2, ErbB2) are two growth factor receptors that have implications in cancer. The overexpression or activation of HER2 occurs frequently in breast, ovarian, and lung cancers, making it an important therapeutic target in the treatment of cancer. Blocking HER2-mediated signaling with antibodies or small molecules has been shown to be effective in inhibiting cell growth. After analyzing the crystal structure of the HER2-herceptin complex, several peptidomimetics (HERP5, 6, and 7) were designed to inhibit HER2-mediated signaling for cell growth. We have used an in silico screening method to investigate the chemical diversity of the designed compounds. autodock software was used to dock the different analogs of HERP5 and HERP7 with HER2 protein extracellular domain. A total of 53 compounds were docked to HER2 protein, and their binding modes were analyzed in terms of docking energy, hydrogen bonding, and hydrophobic interactions. Compounds that exhibited low-energy docked structures were chosen for chemical synthesis and biological activity. Two of the compounds (HERP5 and HERP7) exhibited antiproliferative activity, with IC(50) values of 0.396 microm and 0.143 microm, respectively, against SKBR-3 cell lines (breast cancer cell lines) that overexpress HER2 protein.
