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Investigation of the Role of NFIB and NR4A2 in Resistance to standard Chemotherapy in Triple Negative Breast Cancer

Triple negative breast cancer (TNBC), characterized by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), is the subtype of breast cancer showing the poorest prognosis. Since TNBCs do not respond to anti-estrogen treatments and lack other target therapies, the only available treatment for TNBC is chemotherapy. TNBC patients are initially highly responsive to pre-operative (neoadjuvant) treatment with drugs including taxanes and anthracyclines. However, a lot of TN tumours rapidly develop resistance to a wide variety of chemotherapeutic drugs and continue to progress showing a very poor prognosis.
The studies reported in this thesis are part of a project on triple negative breast cancer, Q-CROC-03, which aims at identifying molecular factors of resistance in TNBCs.
Genomics analysis was on pre and post-chemotherapy TNBCs to determine which molecular factors were enriched for during chemotherapy, i.e. whose expression had increased in the residual post-chemotherapy tumours compared to matched prechemotherapy tumour samples. Here we investigated the functional relevance of NFIB and NR4A2 in doxorubicin or paclitaxel resistance, respectively, of triple negative breast cancers, both of which showed increased expression postchemotherapy.
Nuclear Factor I B (NFIB), a member of the NFI family, is implicated both in activation and in repression of transcription from numerous promoters and has been shown to be an unfavourable prognostic factor in TNBC. An amplicon involving the NFIB gene found in the post chemo specimen of one patient participating to the QCROC- 03 study was also observed in the SUM149 TNBC cell line, suggesting a potential role of this gene in acquisition of drug resistance. In order to understand the biological relevance of NFIB amplification, we examine doxorubicin resistance and cellular migration in NFIB-knockdown SUM149 cells. NFIB knockdown did not affect SUM149 proliferation, doxorubicin resistance, nor did it effect migration in response to insulin, hydrocortisone or FBS. Hence, contrary to what we could expect from studies reported in the literature, our data suggest that, in this particular cell line, NFIB is not involved in the cellular mechanisms examined.
The orphan nuclear receptor NR4A2 is a member of a nuclear receptor superfamily comprising a large number of proteins functioning as transcription factors that control diverse genes participating in a broad spectrum of biological processes, including processes associated with carcinogenesis. NR4A2 showed a >2 fold increased expression in post chemo tumour samples in 6 paired specimens out of 15 and an increased expression of 2.1 (Log2) in the paclitaxel resistant-MDA-MB-436 TNBC cell line versus the parental counterpart. To investigate NR4A2 overexpression impact on paclitaxel resistance, we silenced NR4A2 gene expression in MDA-MB-436 PTXresistance cell line by using siRNAs. Inhibition of NR4A2 expression was accompanied by a reduction in proliferation and by an increase in paclitaxel sensitivity, suggesting a role for NR4A2 in cellular proliferation and paclitaxel resistance in the triple negative breast cancer cell line MDA-MB-436 resistant to paclitaxel.
In conclusion, while our data from NFIB knockdown experiments did not validate our clinical sample data, the findings regarding NR4A2 indicate a potential role for NR4A2 inhibition in TNBC therapy, interfering both with proliferation and drug resistance of PTX-resistant cells. These observations justify further studies on the role of NR4A2 in TNBC PTX-resistant cells.

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10 2 INTRODUCTION 2.1 Breast Cancer Breast cancer (BC) is the second most common cancer in the world and the most frequent among women. According to the most recent data from the web-based platform Global Cancer Observatory (GCO), 1,67 million new breast cancer cases were diagnosed in 2012 (25% of all cancers) worldwide. BC is the fifth cause of death from cancer, with 522000 deaths in the 2012 (12137 in Italy); in the more developed regions BC is, in general, the second cause of cancer death in women, after lung cancer; the first in less developed regions (Globocan 2012). Since the 2008 estimates, by 2012, breast cancer incidence had increased by more than 20%, while mortality had increased by 14%, and the international incidence of female breast cancer will probably reach 3.2 million new cases per year by 2050 (Ziqi et al, 2015). Several risk factors for breast cancer have been well documented; environment, genes, and lifestyle work together to increase or decrease the probability of developing breast cancer. In some cases, it can be a hereditary disease. There are some mutations, as in BRCA1, BRCA2 and p53, which result in a very high risk for breast cancer and which can be passed on from one generation to the next in an autosomal dominant fashion. However, these mutations are rare and account for a small portion of the total breast cancer burden. Some risk factors, the reproductive factors, are associated with prolonged exposure to endogenous oestrogens. These are, for example, early menarche, late menopause and late age at first childbirth. In addition, oral contraceptive and hormone replacement therapy users have been found to be at higher risk than non-users. In contrast, breastfeeding has a protective effect (IARC, 2008; Lacey et al., 2009). Pregnancy also protects against breast cancer probably due to the process of breast tissue differentiation following pregnancy (Ziqi et al, 2015). Age is another risk factor; breast cancer incidence and death rates generally increase with age. Other non-

Tesi di Laurea Magistrale

Facoltà: Scienze Biotecnologiche

Autore: Simona Sala Contatta »

Composta da 100 pagine.

 

Questa tesi ha raggiunto 77 click dal 07/04/2017.

Disponibile in PDF, la consultazione è esclusivamente in formato digitale.