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Replication factor C-40 (RFC40/RFC2) as a prognostic marker and target in estrogen positive and negative and triple negative breast cancer

2015-11-24 20:05:31

United States Patent 9193970; 24 November 2015


Rakhee S. Gupte



Abstract


The present disclosure relates generally to cancer and particularly to breast cancer including estrogen sensitive, estrogen resistant and triple negative breast cancer (TNBC), and to methods of diagnosis and prognosis thereof and therapeutic intervention involving replication factor C 40 (RFC40). Methods and assays for evaluating breast cancer are provided. The disclosure also relates to inhibition or modulation of RFC40 in treatment or alleviation of cancer, including breast cancer. RFC40 inhibitors, including siRNAs and miRNAs, which specifically affect cancer cells, particularly breast cancer cells, are provided.



DESCRIPTION



Field


The present invention relates generally to cancer and particularly to breast cancer including estrogen sensitive, estrogen resistant and triple negative breast cancer (TNBC), and to methods of diagnosis and prognosis thereof and therapeutic intervention involving replication factor C 40 (RFC40). The invention also relates to inhibition or modulation of RFC40 in treatment or alleviation of cancer, including breast cancer.



Background of the Invention


Breast cancer accounts for 18% of all cancers in women, making it the foremost cause of cancer-related deaths in women (McPherson K et al (2000) BMJ 321(7261):624-8). Currently, routine mammography is the most commonly used method for early detection of breast cancer (Smith R A et al (2012) Oncology 26(5):471-5, 479-81, 485-6). Therefore, early diagnosis and treatment of breast cancer could play a monumental role in reducing deaths (Misek D E and Kim E H (2011) Int J Proteomics 2011:343582). Most of the drugs available for the treatment of breast cancers target growth factor and endocrine receptors, particularly the endocrine (estrogen; ER) or growth factor ((ErbB-1, ErbB-2 [human epidermal growth factor receptor 2; HER2], ErbB-3 and ErbB-4) receptors for therapy.


However, emerging resistance to endocrine drugs and therapies targeted against HER2 receptors have created a dire need for identification of molecular targets that are non-receptor based and directly involved in the proliferation of the cancer cells (Normanno N et al (2005) Endocr Relat Cancer 12(4):721-47; Normanno N et al (2009) Endocr Relat Cancer 16(3):675-702). Triple Negative breast cancer (TNBC) is known to be the most aggressive of breast cancers that can metastasis beyond the breast and are more likely to recur after treatment. Tumors and cells of this subtype of breast cancer lack the estrogen, progesterone as well as the human epidermal growth factor receptor 2 and hence will not respond to the traditional therapies. Although, estrogen positive and HER2 over-expressed breast cancers have relatively good target-based agents for treatment, Triple Negative Breast cancer (TNBC) will not respond to these therapies since it lacks all these receptors. There is therefore a huge void for therapies for patients with triple-negative breast cancer (endocrine and growth receptor negative). Hence, the discovery of non receptor based target therapies that may be universally applicable to all subtypes of breast cancers is of paramount importance.



DNA replication is one of the most remarkable and challenging steps in the cell cycle and requires the collaboration of a formidable number of proteins. In eukaryotes, several accessory proteins such as Replication Factor C (RFC) and Proliferating Cell Nuclear Antigen (PCNA), confer speed and high processivity to the replicative polymerases, DNA polymerases ? (Pol ?) and ?. The RFC loads PCNA onto DNA and consists of five subunits, RFC140, RFC40, RFC38, RFC37 and RFC36 (Gupte R S et al (2005) Cell Cycle 4(2): 323-329). Its assembly commits the cell to DNA replication and is involved in many DNA transactions such as DNA damage checkpoint response, maintenance of genomic stability and regulation of sister chromatid cohesion in mitosis as well as in meiosis.



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