Abstract
Plac1 is an X-linked trophoblast gene expressed at high levels in the placenta, but not in adult somatic tissues other than the testis. Plac1 however is re-expressed in several solid tumors and in most human cancer cell lines. To explore the role of Plac1 in cancer progression, Plac1 was reduced by RNA interference in EO771 mammary carcinoma cells. EO771 “knockdown” (KD) resulted in 50% reduction in proliferation in vitro and impaired tumor growth in syngeneic mice; however, tumor growth in SCID mice was equivalent to tumor cells expressing a non-silencing control RNA, suggesting that Plac1 regulated adaptive immunity. Gene expression profiling of Plac1 KD cells indicated reduction in several inflammatory and immune factors, including Cxcl1, Ccl5, Ly6a/Sca-1, Ly6c and Lif. Treatment of mice engrafted with wild-type EO771 cells with a Cxcr2 antagonist impaired tumor growth, reduced myeloid-derived suppressor cells and regulatory T cells, while increasing macrophages, dendritic cells, NK cells and the penetration of CD8+ T cells into the tumor bed. Cxcl1 KD phenocopied the effects of Plac1 KD on tumor growth, and overexpression of Cxcl1 partially rescued Plac1 KD cells. These results reveal that Plac1 modulates a tolerogenic tumor microenvironment in part by modulating the chemokine axis.
Highlights
In the MMTV-PPARd transgenic model of luminal B breast cancer, Plac[1] expression was highly elevated at the onset and throughout mammary tumorigenesis[14], suggesting that it might have a role in the initiation and progression of tumor development
To characterize the functional role of Plac[1], several mouse mammary tumor cell lines were screened by Quantitative real-time polymerase chain reaction (qRT-PCR) for Plac[1] RNA expression; among these, EO771 cells expressed the highest level, which was substantial in comparison to mouse placenta (Fig. 1a)
EO771 cells were transduced with recombinant lentiviruses expressing shRNAs targeting four regions of Plac[1] mRNA (Fig. 1b). shRNA490 produced >98% reduction of Plac[1] expression, and EO771 cells transduced with this shRNA (EO771/shPlac1) were used for further studies
Summary
In the MMTV-PPARd transgenic model of luminal B breast cancer, Plac[1] expression was highly elevated at the onset and throughout mammary tumorigenesis[14], suggesting that it might have a role in the initiation and progression of tumor development. Previous studies found that Plac[1] transcription in human breast cancer cells was regulated by many of the same co-activators associated with PPARd and other nuclear receptors[15,16,17], including C/EBPβ and NCOA318,19, both of which have been implicated in breast cancer progression[16,20,21,22]. Despite these findings, little is known about the oncogenic processes downstream of Plac[1]. Shown are immune cell-related transcripts (Table 1) representing ≥3.0-fold change in expression
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