A majority of breast cancer cases are positive for the estrogen receptor (ER), which means that they can respond to the estrogen hormone to achieve growth. Hence, the ER signaling pathway has been extensively targeted in pharmaceutical research and development in order to suppress tumor growth. However, prevalent hormone therapy and targeted therapy often become ineffective as cancer cells ultimately develop resistance, suggesting that there could be unidentified signaling molecules and events that regulate breast cancer growth. Notably, recent studies have uncovered that Piwi-like (Piwil) proteins, which were initially found in germline cells, are expressed in a wide spectrum of human cancers, including breast cancers. Although Piwil proteins have been well established to silence retrotransposons and to promote heterochromatin formation in germline cells, their somatic functions in cancer cells remain largely unknown. In the present study, we profiled the expression of four Piwi homologs in an ER-positive breast cancer cell line, MCF-7, and found that only Piwil4 was upregulated by 17β-estradiol treatment. Notably, Piwil4 upregulation was not observed in an ER-positive but non-tumorigenic breast cancer cell line, MCF-12A. In addition, the induced expression of Piwil4 was dependent on estrogen/ERα signaling. To explore the biological significance of Piwil4 in breast cancer growth, we knocked down Piwil4 with multiple siRNAs and observed the suppressed expression of some canonical targets of ER. The knockdown of Piwil4 expression also decreased the migration and invasion capabilities of MCF-7 cells. Furthermore, the loss-of-function of Piwil4 reduced the motility of MCF-7 cells in wound-healing assays, which could be associated to decreased expression of vimentin and N-cadherin. Collectively, these findings revealed that Piwil4 is a novel regulator of ER signaling that could be targeted to inhibit breast cancer growth and migration.
Breast cancer is the major cause of cancer-related death in women globally. With the revelation of key molecular pathways modulating all aspects of the breast cancer, the pharmaceutical development and clinical treatment have achieved significant progress. However, patients are still threatened by serious issues, including drug resistance, relapse and metastasis. In addition, a reliable and comprehensive system of early detection of the tumor is still lacking. As such, we set out to identify potential signaling pathway that could serve as novel drug target and diagnostic indicator. Recently, the PIWI (P-element-induced wimpy testis)-like proteins are gaining more interest as prospective biomarkers and targets for therapeutic development because of their re-expression in cancer cells. Initially, the PIWI-like proteins were regarded as germline-specific regulators. They have been revealed to exert important epigenetic functions in germ cells, including the suppression of retrotransposons, the formation of heterochromatin, and the maintenance of DNA methylation status. Surprisingly, in various human tumors, the abnormal expression of PIWI-like proteins was readily observed. The in vitro data showed that the repression of these proteins significantly slowed down the tumor growth, raising an intriguing question whether the PIWI-like proteins and the associated small RNAs, piRNAs, contribute to the breast cancer initiation and progression. In this study, we investigated the expression PIWI-like proteins and piRNAs in three different breast cell lines. It was found that in the normal mammalian epithelial cell line, MCF12A, there was a general lack of PIWI-like expression, which was unaffected by the addition of estrogen. In addition, there was no indication of piRNA generation and accumulation in MCF12A. However, in two breast cancer cell lines, MCF7 and MDA-MB-231, we detected robust expression of PIWI proteins and piRNAs. The knockdown of individual PIWI-like homologs significantly impacted two important indicators of the cancer, rapid proliferation and migration capacity. Furthermore, we found that the depletion of PIWI-like homologs repressed the expression of key regulators of pro-growth genes, such as CCND1, while enhancing those anti-proliferation factors and metastasis inhibitors, such as Bcl-2, p27, p53 and Oct-4. The data indicate that PIWI-like proteins could contribute to cancer formation and progression. We will further explore whether they exert these regulatory functions at the epigenetic level, just like in germ cells. Also, a comprehensive profiling of piRNAs in breast cancer will provide further clue about the clinical potential of using the PIWI/piRNA pathway as a screening indicator. Note: This abstract was not presented at the conference. Citation Format: Jing Yi Lee, Wai Cheong Yip, Qidong Hu. PIWI-like proteins and piRNAs in breast cancer cell proliferation and migration. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A29.
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