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ORIGINAL ARTICLE
Year : 2016  |  Volume : 35  |  Issue : 4  |  Page : 339-347

Livin gene expression in breast carcinoma: correlation with prognostic factors and patient outcome


1 Department of Surgery, Medical Research Institute (MRI), Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Department of Clinical Oncology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Submission26-Mar-2016
Date of Acceptance08-May-2016
Date of Web Publication28-Nov-2016

Correspondence Address:
Khaled E Soliman
165, El Horreya Avenue, Medical Research Institute (MRI), Alexandria, 21525
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1121.194732

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  Abstract 


Background Livin, the most recently identified inhibitor of apoptosis protein, is one of the most tumour-specific genes in the human genome. Its role in breast cancer progression remains unknown.
Aim The aim of the study was to evaluate the expression of livin gene in human breast cancer tissues and examine its correlation with prognostic factors, including patient outcome.
Patients and methods A total of 34 female patients with breast cancer enroled for modified radical mastectomy or conservative breast surgery were included in this study. The surgically resected breast cancer tissue specimens were analysed for the expression of livin protein by immunohistochemistry. All study patients received adjuvant treatment and were followed up for disease-free and overall survival.
Results The positive expression pattern of livin protein was found in 88.2% of breast cancer specimens analysed. Livin gene expression was significantly correlated with tumour size (P≤0.05). No significant correlation was found between livin gene expression and patient age, menstrual status, tumour grade, lymph node metastasis, oestrogen receptor, progesterone receptor hormonal status, and human epidermal growth factor receptor 2 status (P>0.05). No significant association was found between livin gene expression and triple-negative breast cancer cases (P>0.05). There was a significant correlation between livin gene expression and TNM tumour stage (P≤0.05). Patients with livin-positive breast cancer had a poor disease-free survival and a shorter overall survival as compared patients with livin-negative tumours, but the difference was not significant (P>0.05).
Conclusion Overexpression of livin gene may play a prominent role in breast cancer progression. It could be useful as a biomarker in breast cancer therapy.

Keywords: breast carcinoma, immunostaining, livin gene, prognosis


How to cite this article:
Soliman KE, Abdalla DM, Khedr GA. Livin gene expression in breast carcinoma: correlation with prognostic factors and patient outcome. Egypt J Surg 2016;35:339-47

How to cite this URL:
Soliman KE, Abdalla DM, Khedr GA. Livin gene expression in breast carcinoma: correlation with prognostic factors and patient outcome. Egypt J Surg [serial online] 2016 [cited 2020 Jun 4];35:339-47. Available from: http://www.ejs.eg.net/text.asp?2016/35/4/339/194732




  Introduction Top


Among diverse cancer types, breast carcinoma stands out for its increasing incidence rates and high mortality worldwide. Breast cancer is the most common malignancy in women and the second leading cause of female death [1]. During the last two decades, progress has been made in defining some of the critical processes associated with the development and progression of breast cancer. It is now generally accepted that malignant transformation involves genetic and epigenetic changes that derail common regulatory mechanisms and result in uncontrolled cellular proliferation and/or aberrant programmed cell death or apoptosis [2].

Malignant tumour progression consists of different steps, including tumour growth, angiogenesis, tumour cell detachment, epithelial–mesenchymal transition and growth of macrometastasis [3]. Migration of cancer cells is one of the key factors responsible for cancer metastasis. Metastasis is generally associated with progression of malignancy. However, the molecular mechanisms involved in the establishment of metastasis are largely unknown. Therefore, understanding the molecular mechanisms involved in the metastatic process could enable the identification of novel potential targets for development of more effective therapeutic interventions against established metastatic disease [4].

The inhibitors of apoptosis proteins (IAP) are closely correlated with proliferation, apoptosis, motility and metastasis. Livin is the most recently identified IAP and its role in breast cancer progression remains unknown [5]. Livin, also called melanoma IAP or kidney IAP, is one of the most tumour-specific genes in the human genome [6]. Livin is undetectable in most normal differentiated tissues but shows a high level of expression in a wide variety of human cancers, including melanoma, renal cell carcinoma, leukaemia, bladder cancer, prostate cancer, cervical cancer, nasopharyngeal cancer and lung cancer [7].

Livin is a 39 kDa protein consisting of a single baculovirus IAP repeat domain and a RING finger motif, the gene of which spans 4.6 kbp on chromosome 20 at band q13 [8]. The antiapoptotic activity of livin is mediated through the inhibition of caspases-3, −7 and −9 as well as by its E3 ubiquitin-ligase-like activity that promotes degradation of Smac/DIABLO, a critical endogenous regulator of all IAPs [9],[10].

This study is designed to evaluate the expression pattern of livin gene in human breast cancer tissues and to examine its correlation with the prognostic factors, including patient outcome.


  Patients and methods Top


The present work was carried out on a total of 34 newly diagnosed female patients with breast cancer collected from the Department of Surgery, Medical Research Institute Hospital, and Clinical Oncology Department, Main Alexandria University Hospital, Alexandria University, Egypt. The current study was conducted during the period from January 2010 to July 2015. After obtaining approval from the ethics committee, Medical Research Institute, Alexandria University, signed informed consent was obtained from all patients who agreed to participate in this study. Patients who received previous chemotherapy or radiotherapy for breast cancer or any other malignancy were excluded from the study.

Before surgery, all patients provided a full medical history and underwent a thorough clinical examination and routine laboratory investigations including complete blood count, liver function tests, and evaluation of serum alkaline phosphatase. Radiological investigations included bilateral mammography and ultrasound examination of both breasts, plain radiography of the chest, and ultrasound of the abdomen and pelvis. In addition, computed tomography of the chest and abdomen was ordered for all stage III patients. Bone scans were performed for all patients in stage III and as clinically indicated (in cases with localized bone pain and/or elevated serum alkaline phosphatase) for patients in stages I and II. Histopathologic confirmation of the breast mass by fine needle aspiration cytology was required before surgery.

Surgical intervention

Patients underwent surgical intervention in the form of modified radical mastectomy (MRM) in 28 patients and conservative breast surgery in the remaining six patients.

After surgery, the surgical specimens were evaluated at the Pathology Department for histopathological examination and immunohistochemistry. The routine pathologic assessment included tumour size, tumour grade, axillary lymph node involvement, oestrogen (ER) and progesterone (PR) receptor status and human epidermal growth factor receptor (HER-2) expression. For each patient, staging was determined according to the American Joint Committee on Cancer TNM staging system [11].

Immunostaining and evaluation of livin protein expression in breast cancer tissue

Representative paraffin blocks for the tumours were selected, and routine haematoxylin and eosin-stained sections were reviewed for grading the tumours, for detecting lymph node metastasis, and for detecting the presence of ductal carcinoma in situ.

Immunohistochemical assessment of livin expression was done on 5 μm sections from the selected paraffin blocks of the tumour specimens mounted on positively charged slides. The slides were baked overnight at 50°C and then deparaffinized in xylene and rehydrated in decreasing grades of alcohol. Endogenous peroxidase activity was blocked by a 20 min treatment with 30% hydrogen peroxide in absolute methanol. The tissue was then preheated in a pressure cooker (20 min in citrate buffer at pH 6). The rabbit polyvalent antilivin antibody used in this study was ab97350. The antibody was incubated overnight at 4°C (dilutions: 1 : 100) in PBS (pH, 7.2). The bound antibody was detected by the Ultra Vision Detection System Antipolyvalent, HRP/DAB (Ready-To-Use; Thermo Scientific, Chicago, USA). Negative and positive controls were included in all runs.

The immunohistochemical staining of livin protein was graded according to the percentage of livin-positive cells in the breast carcinoma cells: grade 0 (negative), ≤5%; grade 1, 5–25%; grade 2, 25–50%; and grade 3, ≥50%. The staining intensity of positive cells was classified into four grades: grade 0 (negative), colourless; grade 1, faint yellow; grade 2, light brown; and grade 3, puce. The integrated immunohistochemical staining results were scored by multiplying the percentage of positive cells by the staining intensity: score 0–1, negative; score 2–3, mildly positive; score 4–6, moderately positive; and score 7–9, strongly positive. Livin expression was mainly cytoplasmic, with a little nuclear; only cytoplasmic staining was measured [12].

Adjuvant therapy and follow-up

All study patients received their adjuvant treatment at the Alexandria Clinical Oncology Department, Alexandria Main University Hospital. Adjuvant treatment was determined on the basis of patient and disease characteristics including age, menopausal status, presence or absence of comorbidities, left ventricular ejection fraction, TNM stage, ER, PR and HER-2 status. Adjuvant treatment included chemotherapy, radiotherapy and hormonal therapy as indicated (http://www.nccn.org/professionals/physicians_gls/pdf/breast.pdf). Patients started their adjuvant chemotherapy 4 to 6 weeks after surgery. Radiation therapy when indicated was given after chemotherapy. Node-positive patients with MRM received radiotherapy to the chest wall and regional lymph nodes. Node-negative patients with MRM and tumour size greater than 5 cm received radiotherapy, whereas patients with tumour measuring less than 5 cm did not receive radiotherapy. All patients who underwent conservative breast surgery received adjuvant radiotherapy. Patients with ER-positive tumour and/or PR-positive tumour received adjuvant hormonal therapy for 5 years.

Patient follow-up included history and physical examination one to four times a year as clinically indicated and then annually. Mammography was performed every 12 months. Patients with signs and symptoms indicating recurrence or metastasis underwent appropriate laboratory and imaging studies. Patients on tamoxifen underwent annual gynaecologic assessment and those on aromatase inhibitors underwent periodic assessment of bone mineral density (http://www.nccn.org/professionals/physicians_gls/pdf/breast.pdf).

Statistical analysis

Data were fed into the computer and all statistical analyses were performed using the statistical package for the social sciences, version 20.0 software for windows (SPSS Inc., Chicago, Illinois, USA). Correlations between livin protein immunoreactivity score and clinicopathological variables were analysed using the χ2-test. To test the significance between groups, Monte Carlo or Fisher’s exact tests were used. Overall survival (OS) was determined considering death as the endpoint, and disease-free survival (DFS)was determined considering metastasis or relapse as the endpoint. The survival curves were calculated by the Kaplan–Meier method based on the log-rank test. A P-value less than or equal to 0.05 was considered statistically significant.


  Results Top


The current study was conducted on a total of 34 female patients with pathologically proven breast cancer. They had an average age ranging from 24 to 73 years with a mean age of 51.46±11.32 years.

In the current study, the histopathological examination of breast carcinoma specimens using haematoxylin and eosin staining revealed that 32 out of 34 breast cancer patients had infiltrating ductal carcinoma (94.12%), whereas the remaining two patients (5.88%) had invasive lobular carcinoma.

By immunohistochemistry, the immunohistochemical staining of livin protein in breast cancer tissue revealed that it was expressed predominantly in the cytoplasm of tumour cells, with little nuclear staining. For further analysis of the study, only the staining of the cytoplasmic livin expression was measured and evaluated in the present work.

The present study demonstrated that 30 out of 34 cases of breast carcinoma specimens (88.2%) were positive for livin gene immunoreactivity. The positive expression pattern of livin protein was graded as mild expression [detected in 10 out of 30 cases (33.3%)], moderate expression [detected in 14 out of 30 cases (46.7%)] and strong livin gene expression [observed in six out of 30 cases (20%)]; four out of 34 cases (11.8%) were negative for livin gene expression ([Figure 1]) The correlation between livin gene expression and clinicopathological parameters of breast cancer is illustrated in [Table 1].
Figure 1 Three representative samples of livin protein immuonoreactivity, assessed by immunohistochemical staining, in breast cancer patients: (a) mild cytoplasmic and nuclear livin positivity in infiltrating ductal carcinoma (+) (×400); (b) moderate cytoplasmic and nuclear livin positivity in infiltrating ductal carcinoma (++) (×400); (c) strong cytoplasmic and nuclear livin positivity in infiltrating ductal carcinoma (+++) (×400).

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Table 1 Correlation between livin gene expression and clinicopathological parameters of breast cancer

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In our study, according to menstrual status, 18 patients (52.94%) were premenopausal, and 16 patients (47.06%) were menopausal. Statistical analysis revealed that there was no significant correlation between livin gene expression and patient age or menstrual status.

As regards tumour size (T), livin gene expression was positive in 33.3% of breast carcinoma specimens (10 out of 30 cases) more than 2 cm to less than or equal to 5 cm in size (T2), whereas livin protein expression was observed in 66.7% (20 out of 30 cases) of tumours more than 5 cm in size (T3). In contrast, livin gene was negatively expressed in all tumour specimens (four cases) having tumour size less than or equal to 2 cm (T1). Statistical analysis revealed that the rate of livin gene expression was significantly higher in tumours more than 5 cm in size than in tumours more than 2 cm to less than or equal to 5 cm in size and livin gene expression was significantly correlated with tumour size (P≤0.05)

Regarding the tumour grade, the histopathological examination of breast cancer tissue specimens revealed that 14 patients (41.18%) were of grade I (well differentiated), 14 patients (41.18%) were of grade II (moderately differentiated) and six patients (17.64) were of grade III (poorly differentiated).

Livin gene expression was found in 14 out of 30 cases (46.7%) in grade I tumours (four mild +, nine moderate ++, and one strong +++); in grade II tumours it was expressed in 10 out of 30 cases (33.3%) (five mild +, two moderate ++, and three strong +++), whereas in grade III tumours it was expressed in six out of 30 cases (20%) (one mild +, three moderate ++, and two strong +++). Statistical analysis revealed that there was no statistically significant correlation between livin gene expression and tumour grade (P>0.05).

Concerning lymph node involvement, the histopathological examination of axillary lymph nodes showed that livin protein was expressed in 22 out of 24 node-positive patients (91.7%) and in eight out of 10 node-negative patients (80%). Statistical analysis showed no significant correlation between livin gene expression and lymph node metastasis (P>0.05)

As regards ER status, the histopathological examination of breast cancer tissue revealed that livin protein expression was observed in 15 out of 18 cases with ER-positive tumours (83.3%) and in 15 out of 16 cases with ER-negative tumours (93.75%).

Regarding PR status, livin protein was expressed in 14 out of 15 cases with PR-positive tumours (93.3%) and in 16 out of 19 cases with PR-negative tumours (84.2%).

According to HER-2 status, livin gene was expressed in all four patients (100%) with HER-2-positive tumours and in 26 out of 30 cases (86.7%) with HER-2-negative tumours.

Statistical analysis showed that there was no statistically significant correlation between livin gene expression and ER, PR and HER-2 status (P>0.05).

Furthermore, livin gene was expressed in 11 out of 34 cases (32.4%) with triple-negative breast cancer disease (TNBC). No statistically significant association was found between livin gene expression and TNBC (P>0.05).

According to TNM classification at the time of diagnosis, two patients (5.9%) were stage I, eight patients (23.5%) were stage II, and 24 patients (70.6%) were stage III. Livin gene expression was observed in all eight patients at stage II (26.7%) and in 22 patients with stage III breast cancer (73.3%). There was a statistically significant correlation between livin gene expression and tumour stage (P≤0.05)

Concerning adjuvant treatment, all study patients received adjuvant chemotherapy: four (11.8%) patients received cyclophosphamide, methotrexate, 5-flurouracil (CMF), 20 (58.8%) patients received 5-flurouracil, adriamycin, cyclophosphamide (FAC), and 10 (29.4%) patients received AC/Taxol. Adjuvant radiotherapy was delivered to 24 (70.6%) patients. Adjuvant hormonal therapy was offered to 20 (58.8%) patients, whereas 14 patients did not receive hormonal therapy because they had both ER-negative and PR-negative disease.

In the present work, all patients were followed up for 5 years. By the end of this period, the 5-year DFS was 100% for livin-negative breast cancer patients as compared with 56.7% (17 out of 30 patients) for livin-positive patients. Relapse was identified as either local recurrence, lymph nodes and/or development of liver or pulmonary metastases. In our series, local recurrence was encountered in 30% (nine out of 30 patients) of cases, whereas four out of 30 patients (13.3%) developed liver and lung metastases.

The 5-year OS was 75% (three out of four patients) in livin-negative breast cancer patients as compared with 73.3% (22 out of 30 patients) in livin-positive patients.

Kaplan–Meier survival curves were plotted for both DES and OS and checked by the log-rank test. Statistical analysis revealed that there was no statistically significant correlation between livin gene expression in breast cancer patients and both DFS and OS (P>0.05) ([Figure 2] and [Figure 3]).
Figure 2 Kaplan–Meier survival curve for disease-free survival.

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Figure 3 Kaplan–Meier survival curve for overall survival.

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  Discussion Top


Breast carcinoma is the most common dreadful malignancy in women. The prediction of clinical outcome in patients with breast cancer is difficult and usually based on clinicopathologic variables such as tumour stage, histologic grade and the presence of metastasis to regional lymph nodes and distant organs [13]. Despite improvements in treatment modalities, there is still a high failure rate mainly due to tumour invasion and metastasis [14]. The regulation of cell migration, invasion and proliferation is crucial for maintaining cellular homoeostasis and its loss is a principal hallmark of cancer cells [4]. Cell proliferation and cell death must be properly balanced to maintain tissue homoeostasis. However, cancer development and progression result from the imbalance between cell proliferation and cell death, most of which occur through apoptosis [15],[16]. In addition, cancer cells are typically characterized by increased resistance to apoptosis and cell cycle control [17].

Livin is considered one of the most important and potent members of the IAP family. It promotes invasion, growth and apoptotic resistance in a variety of human cancer cells [6],[7],[18]. Livin overexpression is associated with tumour progression, more aggressive tumour behaviour such as migration, and resistance to radiotherapy as well as to chemotherapy in several types of human cancers [19],[20],[21]. Identification of molecular targets and signalling pathways involved in cancer progression is therefore relevant to therapy.Thus, it is important to identify the molecular determinants that mediate the apoptotic resistance of breast cancer cells in order to develop novel and more effective therapeutic strategies [22].

In the current study, by immunohistochemistry, we evaluated the expression pattern of livin protein and its prognostic relevance in a series of human breast cancer tissues with their clinicopathological data, including survival. In our series, we found extensive expression [88.2% (30/34)] of livin protein in the breast cancer tissue specimens analysed. The prevalent expression of livin protein in breast cancer tissues and cells suggested that it plays a prominent role in the progression of breast cancer. Previous studies reported that livin gene was expressed at different rates in various human cancers as in the study by Liu et al. [23], who stated that livin expression was observed in 19 out of 40 gastric cancer cases (47.5%). Hinz et al. [24] reported that livin expression was detected in 38.8% (59/152) of renal cell carcinoma specimens, whereas Song et al. [25] demonstrated that the overall positive rate of livin in 60 cases of transitional cell carcinoma of the bladder was 28.3% (17/60). Moreover, Kim et al. [20] reported that livin expression was observed in 79.5% (54/68) of neuroblastoma cases. The discrepancy with other authors may be attributed to different scoring systems, different antibodies used and a relatively small sample size. Also, dysfunction of genes is caused by a complex process of genetic mutations, epigenetic alteration and post-transcriptional modification.

In the present work, analysis of the patients’ clinicopathological data revealed that the expression of livin in breast cancer was not closely related to age, menstrual status, histopathological grade, ER, PR, or HER-2 status or TNBC, confirming the findings obtained by previous publications [26].

In our study, we found a statistically significant correlation between livin protein expression and the size of the primary tumour. Livin gene expression was more frequently observed in livin-expressing breast cancer tumours of larger size (>5 cm) versus smaller tumours, suggesting that advanced-stage breast cancer expresses a high level of livin protein. In a recent report, Lazar et al. [27] stated that livin protein expression in melanoma patients was associated with tumour size, and the melanoma with a smaller diameter expresses a higher level of livin protein, suggesting that early-stage melanoma expresses a high level of livin protein. Another study reported that hepatocellular carcinoma with a smaller diameter tends to express higher levels of livin protein; however, no significant difference was detected [12].

Concerning the lymph node status in our series, there was no statistically significant association between livin gene expression and lymph node metastases. Our findings were in association with those reported by Wang et al. [28], who demonstrated that livin gene expression in colorectal cancer was not related to lymph node metastasis. In contrast, Liu et al. [23] and Liang et al. [29] reported a positive correlation between livin gene expression and lymph node metastasis in gastric cancer. A recent study reported that livin expression increased as lymph node metastasis increased and as breast cancer severity increased [26].

The current study showed that there was a statistically significant correlation between livin gene expression and tumour stage. The positive expression rate of livin in TNM breast cancer stage III (73.3%) was higher than that in stage II (26.7%). Increased livin expression in human breast cancer was related to the more advanced stage of cancer, which is indicative of poor prognosis. In agreement with our results, Myung et al. [30] stated that livin immunostaining was significantly associated with tumour stage, lymphovascular invasion and lymph node metastasis in patients with colorectal cancer. Likewise, Xue et al. [31] found that high livin expression correlated with cell differentiation, tumour node metastasis stage and lymph node metastasis in human ampullary carcinoma. In contrast, Zhao et al. [32] stated that the expression of livin mRNA had no correlation to TNM stage in human gastric carcinomas. Moreover, no significant difference in livin protein expression and clinical tumour stage has been found in previous publications [25],[28].

In the present work, we examined the relationship between livin gene expression and survival in patients with breast cancer and found that increased livin expression in tumours was associated with poor DFS and a shorter OS, although the difference was not statistically significant. Controversies remained on the prognostic value of livin gene in different tumour types. A recent study stated that livin protein overexpression together with amplified Myc oncogene in patients with neuroblastoma predicted a poor prognosis [20]. Gazzaniga et al. [33] demonstrated that, in a proportion of superficial bladder cancer patients, increased livin expression in tumours was associated with shorter duration of relapse-free survival. Moreover, previous authors reported that livin expression was also parallel with a decreased OS in osteosarcoma patients [34]. Our results were consistent with previous reports and suggest that livin expression may help predict the poor clinical outcome of human breast cancer.

In contrast, although most studies supported the negative impact of livin gene on survival, mild influence or even favourable prognosis was also reported. Recently, Choi et al. [35] stated that livin expression promoted apoptotic response in leukaemic cells, which is induced by chemotherapeutic agents, and concluded that it was an independent favourable prognostic factor in childhood acute lymphoblastic leukaemia. Other investigators demonstrated that high nuclear livin protein expression predicted satisfactory prognosis of renal cell carcinoma [36]. In contrast, in a study of nasopharyngeal carcinoma, livin expression was detected in 48% of tumours by immunohistochemistry, and livin expression did not predict DFS or OS [37]. Similar results were also reported by previous publications [38].

In summary, it would be reasonable to suggest that the prognostic significance of livin is tissue and tumour specific.

Although the majority of literature findings indicate a future significance of livin as a biomarker for different cancers with clinical relevance, more research into the molecular aspects is crucial to particularly evaluate the major function of livin in the process of tumorigenesis. Furthermore, understanding the expression pattern and function of livin protein in a wide variety of cancerous tissues can provide valuable new diagnostic, prognostic and therapeutic approaches to tackle this deadly disease.

Livin inhibits apoptosis and its overexpression renders malignant cells resistant to chemotherapy. Downregulation of livin expression increases the apoptotic rate, reduces tumour growth potential and sensitizes tumour cells to chemotherapeutic drugs. Therefore, livin-specific chemical inhibitors could be useful adjuncts to chemotherapy in the treatment of malignancies [6].

Thus, utilizing livin as an anticancer target could generate a plethora of therapeutically pertinent opportunities to overcome the current predicaments in cancer therapy.

A large body of evidence now supports the important functions of livin expression in the progression of cancer. Although the details of the multiple pathways emanating from livin networks are yet to be fully elucidated, there is a consensus that livin is an appropriate therapeutic target for effective cancer therapy. However, full verification of livin application will come from preclinical and clinical trials taking into consideration both biological and clinical efficacy endpoints in larger, diverse populations. It is hoped that the potential approaches that future studies develop will bring more benefits to patients with malignancy.

Finally, we conclude that the high expression pattern of livin gene in breast carcinoma may play a prominent role in disease progression. Livin expression may help predict poor clinical outcome and could be useful as a molecular biomarker and therapeutic target for effective breast cancer therapy.

Financial support and sponsorship

NilConflicts of interest

There are no conflicts of interest.

 
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    Figures

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