FANCD2 and BRCA1 have differential expression among the FA-BRCA genes in primary breast cancer/ Expressão diferencial de FANCD2 e BRCA1 no câncer de mama primário

Sarah Franco Vieira de Oliveira Maciel, Leandro Tamião Rodrigues Serino, Luis Gustavo Sá- Gabriel, Marcos Euzébio Maciel, Cícero de Andrade Urban, Rubens Silveira de Lima, Iglenir João Cavalli, Enilze Maria de Souza Fonseca Ribeiro

Abstract


The molecular pathways of DNA repair in tumors may play a role in tailoring patient therapy. The Fanconi anemia DNA repair pathway operates in the repair of DNA interstrand crosslink induced by several chemotherapeutic drugs. In this study we evaluated the expression of Fanconi anemia DNA repair genes (FANCA, C, D2, F, BRCA1 and PALB2) in 46 primary breast tumors and ten non-compromised breast samples, by Real-Time Quantitative Reverse Transcription PCR, and to correlated gene expression with breast cancer subtypes and clinico-pathological parameters. Tumor samples were classified in subtypes based on immunohistochemistry markers, and clinico-pathological parameters were obtained from the medical reports. FANCD2 was twice more expressed in tumors than in the non-compromised group (p= 0.02). BRCA1 showed a differential expression in the luminal group, three times less expressed in Luminal-B than in Luminal-A group (p= 0.01). In conclusion, the higher level of expression of FANCD2 in tumors may indicate activation of the Fanconi anemia DNA repair pathway, which has been implicated in breast carcinogenesis and in chemotherapeutic resistance. The loss of BRCA1 expression in the Luminal-B group may indicate that the use of cisplatin-based neo/adjuvant therapies is preferable, and that the use of taxol-based therapies should be avoided due to the risk of drug resistance.


Keywords


DNA repair, FANCD2, BRCA1, gene expression, breast cancer.

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References


Alan, D., D’Andrea, M.D. (2010) The Fanconi Anemia and Breast Cancer Susceptibility Pathways. N Engl J Med, 362, 1909–1919.

Altieri, F., Grillo, C., Maceroni, M., Chichiarelli, S. (2008). DNA Damage and Repair: From Molecular Mechanisms to Health Implications. Antioxidants Redox Signaling, 10, 891-937.

Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A., Jemal, A. (2018). Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 0, 1-31.

Bryant, H.E., Helleday, T. (2006). Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair. Nucleic acids res, 34, 1685–1691.

Castralli, H.A., Bayer, V.M.L. (2019). Breast cancer with genetic etiology of mutation in BRCA1 and BRCA2: a synthesis of the literature. Braz. J. Hea. Rev., 2, 2215-2224.

Chen, C.C., Taniguchi, T., D’Andrea, A. (2007). The Fanconi anemia (FA) pathway confers glioma resistance to DNA alkylating agents. J Mol Med, 85, 497–509.

Condie, A., Powles, R.L., Hudson, C.D., et al. (2002). Analysis of the Fanconi anaemia complementation group A gene in acute myeloid leukaemia. Leuk Lymphoma, 43, 1849–1853.

Deans, A.J., West, S.C. (2011). DNA interstrand crosslink repair and cancer. Nat Rev Cancer, 11, 467–480.

Doane, A.S., Danso, M., Lal, P., et al. (2006). An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene, 25, 3994–4008.

Dorsman, J.C., Levitus, M., Rockx, D., et al. (2007). Identification of the Fanconi anemia complementation group I gene, FANCI. Cell Oncol, 29, 211–218.

Duan, W., Gao, L., Zhao, W., et al. (2013). Assessment of FANCD2 nuclear foci formation in paraffin-embedded tumors: a potential patient- enrichment strategy for treatment with DNA interstrand crosslinking agents. Translational Research, 161, 156–164.

Durkin, S.G., Glover, T.W. (2007). Chromosome fragile sites. Annu Rev Genet, 41, 169–192.

Edwards, S.L., Brough, R., Lord, C.J., et al. (2008). Resistance to therapy caused by intragenic deletion in BRCA2. Nature, 451, 1111–1115.

Fong, P.C., Boss, D.S., Yap, T.A., et al. (2009). Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med, 361, 123–134.

Ganzinelli, M., Mariani, P., Cattaneo, D., et al. (2011). Expression of DNA repair genes in ovarian cancer samples: Biological and clinical considerations. Eur J Cancer, 47, 1086-1094.

Gao, Y., Zhu, J., Zhang, X., et al. (2013). BRCA1 mRNA Expression as a Predictive and Prognostic Marker in Advanced Esophageal Squamous Cell Carcinoma Treated with Cisplatin- or Docetaxel-Based Chemotherapy/Chemoradiotherapy. PloS ONE, 8, e52589

Goldhirsch, A., Winer, E.P., Coates, A.S., et al. (2013). Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Annals of Oncology, 24, 2206–2223.

Hoskins, E.E., Gunawardena, R.W., Habash, K.B., et al. (2008). Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway. Oncogene, 27, 4798–4808.

Instituto Nacional do Cancer – INCA (2020, February 28). Retrieved from http://www.inca.gov.br/estimativa/2020/sintese-de-resultados-comentarios.asp

Jones, R.L., Constantinidou, A., Reis-Filho, J.S. (2012). Molecular Classification of Breast Cancer. Surgical Pathology, 5, 701–717.

Kao, W.H., Riker, A.I., Kushwaha, D.S., et al. (2011). Upregulation of Fanconi Anemia DNA Repair Genes in Melanoma Compared to Non-Melanoma Skin Cancer. J Invest Dermatol, 10, 2139–2142.

Kee, Y., D’Andrea, A.D. (2010). Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Genes Dev, 24, 1680–1694.

Kim, J., Kim, M.A., Min, S.Y., Jee, C.D., Lee, H.E., Kim, W.H. (2011). Downregulation of Methylthioadenosina Phosphorylase by Homozygous Deletion in Gastric Carcinoma. Genes, Chromosomes Cancer, 50, 421-433.

Kumar, M., Sahu, R.K., Goyal, A., et al. (2017). BRCA1 Promoter Methylation and Expression - Associations with ER+, PR+ and HER2+ Subtypes of Breast Carcinoma. Asian Pac J Cancer Prev, 18, 3293-3299.

Lambie, H., Miremadi, A., Pinder, S.E., et al. (2003). Prognostic significance of BRCA1 expression in sporadic breast carcinomas. J Pathol, 200, 207–213.

Mathew, C.G. (2006). Fanconi anaemia genes and susceptibility to cancer. Oncogene, 25, 5875–5884.

Nalepa, G., Clapp, D.W. (2018). Fanconi anaemia and cancer: an intricate relationship. Nat Rev Can, 3, 168-185.

Nepal, M., Che, R., Zhang, J., Ma, C., Fei, P. (2017). Fanconi Anemia Signaling and Cancer. Trends Cancer, 3, 840–856.

Nitta, M., Kozono, D., Kennedy, R., et al. (2010). Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy. PloS ONE, 5, e10767.

Noll, D.M., Mason, T.M., Miller, P.S. (2006). Formation and repair of interstrand cross-links in DNA. Chem Rev, 106, 277–301.

Ozawa, H., Iwatsuki, M., Mimori, K., et al. (2010). FANCD2 mRNA Overexpression is a Bona Fide Indicator of Lymph Node Metastasis in Human Colorectal Cancer. Ann Surg Oncol, 17, 2341–2348.

Pejovic, T., Yates, J.E., Liu, H.Y., et al. (2006). Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer. Cancer Res, 66, 9017–9025.

Ribeiro, E., Ganzinelli, M., Andreis, D., et al. (2013). Triple Negative Breast Cancers Have a Reduced Expression of DNA Repair Genes. PloS ONE, 8, e66243.

Rudland, P.S., Platt-Higgins, A.M., Davies, L.M., et al. (2010). Significance of the Fanconi Anemia FANCD2 Protein in Sporadic and Metastatic Human Breast Cancer. Am J Pathol, 176, 2935-2947.

Silva, W.S., Bacciotti, A.M., Almeida, E.R.N., Rocha, F.S. (2020). Immunohistochemical profile and treatments performed in patients with breast cancer care at a reference hospital in the north region. Braz. J. Hea. Rev., 3, 6811-6822.

Smeaton, M.B., Hlavin, E.M., McGregor, M.T., Noronha, A.M., Wilds, C.J., Miller, P.S. (2008). Distortion-dependent unhooking of interstrand cross-links in mammalian cell extracts. Biochemistry, 47, 9920–9930.

Taniguchi, T., Garcia-Higuera, I., Andreassen, P.R., Gregory, R.C., Grompe, M., D’Andrea, A.D. (2002). S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Blood, 100, 2414–2420.

Torre, L.A., Bray, F.; Siegel, R.L., Ferlay, J., Lortet-Tieulent, J,. Jemal, A. (2015). Global Cancer Statistics. CA Cancer J Clin, 65, 87-108.

Van der Groep, P., Hoelzel, M., Buerger, H., Joenje, H., De Winter, J.P., Van Diest, P.J. (2008). Loss of expression of FANCD2 protein in sporadic and hereditary breast cancer. Breast Cancer Res Treat, 107, 41–47.

Verma, D., Agarwal, D., Tudu, S.K. (2018). Expression of breast cancer type 1 and its relation with expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2/neu in breast carcinoma on trucut biopsy specimens. Indian Journal of Pathology and Microbiology, 1, 31-38.

Yarde, D.N., Oliveira, V., Mathews, L., et al. (2009). Targeting the Fanconi anemia/ BRCA pathway circumvents drug resistance in multiple myeloma. Cancer Res, 69, 9367–9375.

Yuanming, L., Lineng, Z., Baorong, S., Junjie, P., Sanjun, C. (2013). BRCA1 and ERCC1 mRNA levels are associated with lymph node metastasis in Chinese patients with colorectal cancer. BMC Cancer, 13, 103.

Zhang, B., Chen, R., Lu, J., Shi, Q., Zhang, X., Chen, J. (2010). Expression of FANCD2 in Sporadic Breast Cancer and Clinicopathological Analysis. J Huazhong Univ Sci Technol, 3, 322-325.

Zhang, Q., Zhang, Q., Cong, H., Zhang, X. (2012). The ectopic expression of BRCA1 is associated with genesis, progression, and prognosis of breast cancer in young patients. Diagnostic Pathology, 7, 181.




DOI: https://doi.org/10.34119/bjhrv3n4-056

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