Intense staining of tissues indicated the KPT-330 clinical trial higher expression of these proteins associated with ER�� (+) breast tumors. To further investigate the potential role of these signatures in ER�� (+) breast cancer, we analysed the expression of these genes in estrogen responsive and tamoxifen sensitive T47D cell line.36 We found that four out of six genes (SLC7A8, ENPP1, LAMB2, and PLAT) were regulated by estrogen. Moreover, the estrogen response was abolished by ICI 182780 treatment for all four genes but tamoxifen could only reduce the expression of PLAT. Our findings that only few genes are estrogen responsive in cell culture are in line with earlier reports.25 There are several possible explanations for these findings. The existence of other ER-signaling pathways, independent of estrogen has been postulated.
37,38 The observation that these transcriptional activities are manifested in a tissue selective manner suggests that the receptor does not function in isolation, but rather, requires specific cellular factors for maximal responses. The complex network of coactivators and corepressors provide balanced, and sensitive control of ER target gene expression.39 NTN4 is a secreted molecule with roles in axon guidance and angiogenesis. NTN4 acts as an antiangiogenic factor through binding to neogenin and recruitment of UNC5B.40 The NTN4 expression is associated with longer disease-free survival and overall survival in breast cancer patients.41 The Shennan��s study confirms that MCF-7 cells express LAT1 and SLC7A8 (LAT2) mRNA but MDA-MB-231 cells express only LAT1 mRNA.
A SLC7A8 expression and activity in MCF-7 cells is also up-regulated by 17��-estradiol and could contribute to the proliferative capacity by increasing amino acid uptake via systems A and L.42,43 Our study confirms the above observation with higher expression of SLC7A8 in ER�� (+) than ER�� (?) breast cancer patients. The MLPH gene encodes a member of the exophilin subfamily of RAB effector proteins.44 The low expression of ER, PgR, HER2 and MLPH genes expression was reported in basal-like subtypes in high risk breast cancer patients.45 Another study reported down regulation of MLPH gene in lymph node positive breast cancer patients.24 Our study confirms the lower expression of MLPH in ER�� (?) breast cancer patients.
A study revealed that ENPP1 was a downstream target of AR (Androgen receptor) and expression of ENPP1 Entinostat might play a potential role in the development of androgen-refractory prostate cancer. ENPP1 over expression also promoted the tumorigenic phenotype in vitro and in vivo during androgen-depleted condition.46 The other study showed expression of ENPP1 as a positive regulator in the Akt signaling pathway.47LAMB2 belongs to the laminin family and are secretory proteins localized to the extra-cellular matrix and basement membrane in breast tissues.