PTEN Gen Yolağı ve Meme Kanseri Arasındaki İlişki

Abstract

Dünya genelinde meme kanseri kadınlarda en yaygın görülen ve en yüksek mortalite oranına sahip kanserdir. Protein tirozin fosfotaz ve tensin homoloğu (PTEN) geni hücre büyümesi, proliferasyon ve migrasyon gibi birçok hücresel fonksiyonu düzenleyen kromozomun 10q23 bölgesinde lokalize tümör baskılayıcı bir gendir. PTEN gen mutasyonları ve somatik delesyonları meme kanseri de dahil birçok kanserde görülmektedir. Sporadik meme kanserlerinin %5’inde PTEN mutasyonlarına rastlanmıştır. Ayrıca PTEN genindeki kalıtsal mutasyonlar Cowden hastalığı olarak bilinen ve tüm yaşam boyunca meme kanseri gelişme riski %25-50 arasında olan nadir, otozomal dominant, ailesel kanser sendromları ile de ilişkilidir. Cowden sendromu taşıyan ailelerin %80’inde PTEN germline mutasyonları mevcuttur. 10q23 bölgesindeki yüksek heterozigot kaybı frekansı ve mutasyon durumu bulunmayan protein ekspresyon kaybı PTEN geninde başka inaktivasyon mekanizmalarının da etkili olduğu sonucunu desteklemektedir. Promotor bölge içindeki sitozin-guanin (CpG) bölgelerindeki hipermetilasyonlar gibi epigenetik olayların bu mekanizmalardan biri olabileceği düşünülmüştür. PTEN, fosfatidilinositol 3-kinaz/protein kinaz B yolağını inhibe ederek hücre büyümesi ve hücre proliferasyonunu azaltır. PTENkaybı BRCA1 mutasyonlu meme kanserleri ile ilişkilidir ve homozigot delesyonlar, DNA çift zincir kırıklarını kapsayan genom instabilitesi ile sonuçlanabilir. PTEN’in DNA tamiri ve farklı dokulardaki DNA hasar tepkisinin anlaşılması PTEN’in genomik stabiliteyi dengelemesini sağlayan moleküler mekanizmaların anlaşılmasını sağlayacaktır. Tümör baskılayıcı gen olan BRCA1 ve PTEN arasındaki bağlantının anlaşılması kansere karşı daha iyi tedavi stratejilerinin oluşturulması ve etkili ajanların keşfedilmesine olanak sağlayacaktır. Bu derlemeyi hazırlamamızdaki temel amaç; PTENgeninin meme kanserindeki önemini vurgulamak ve PTEN yolağı ve bu yolağın diğer yolaklarla ilişkilerini açıklayarak meme kanserinde yeni hedef tedavilerin geliştirilmesidir.

Keywords

• Meme Kanseri
• PTEN Geni
• BRCA1 Geni

PTEN Gen Yolağı ve Meme Kanseri Arasındaki İlişki

Abstract

Breast cancer is the most common malignancy with a high mortality in females worldwide. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene located on chromosomal band 10q23 and regulates many cellular functions including cell growth, proliferation, and migration. Somatic deletions and/or mutations of PTEN gene is commonly seen in several cancers including breast cancer. PTEN mutations have been found in only 5% of sporadic breast cancers. Germline mutations of the PTEN gene are associated with a rare, autosomal-dominant, familial cancer syndrome known as Cowden disease, which is associated with a 25 to 50% lifetime risk of developing breast cancer. In families with Cowden sendrome, 80% have PTEN germline mutations. The high frequency of loss of heterozygosity in 10q23 and the loss of protein expression without a comparable mutational status suggest there should be other inactivation mechanisms of the PTEN gene. Epigenetic events, such as hypermethylation of cytosine-guanine (CpG) sites in the promoter region, could be one mechanism. PTEN inhibits the phosphatidylinositol 3-kinase/protein kinase B pathway, whose inhibition eventually reduces cell growth and cell proliferation. PTEN loss is highly associated with BRCA1 breast cancers, which could result from genome instability involving homozygous deletions, DNA double-strand breaks and so on. Further detailed mechanistic understanding of the roles of PTEN in DNA repair and DNA damage response in different tissues and cell types will help us fully understand the pre- cise molecular mechanisms by which PTEN maintains genomic stability and contributes to tumor suppression and therapeutic efficacy. Understanding the connection between tumor suppressor BRCA1 and PTEN would facilitate the development of effective agents and strategies to better treatment against cancer. The main purpose of our preparation of this review to emphasize the importance of PTEN gene in breast cancer and PTEN pathway and the development of new targeted therapies in breast cancer by explaining the relationship between this pathway and other pathways.

Keywords

• Breast Cancer
• PTEN Gene
• BRCA1 Gene

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