Breast carcinoma is the most common malignant tumor and the leading cause of carcinoma death in women with a tremendous heterogeneity in its clinical behavior. According to data from the Cancer Registry of Tunisia, breast carcinoma is the most frequent malignant neoplasm affecting Tunisian female patients with an incidence of 23.6/100.000 inhabitants 1. The data of our registry show that women with breast carcinoma in Tunisia are relatively younger than in Western countries, with an average age of 51 years 2. The incidence standardized on the age of the cancer of the breast in Tunisia was 16.7/100,000 women) 3. This may suggest that breast carcinoma in Tunisia may have some biological features that need to be explored. Besides, the increasing incidence and significant breast cancer mortality (Overall survival rate = 50.5% after 5 years) 4 highlight the need for new therapeutic development, especially targeted treatment. A humanized monoclonal antibody, trastuzumab (Herceptin), targeting the human epidermal growth factor receptor 2 (HER-2) gene is a prime example of this new class of treatment. The (HER-2) gene is localized on chromosome 17q. It encodes for a transmembrane tyrosine kinase receptor protein that is a member of the HER family. HER-2 gene amplification is found in 10–34% of invasive breast carcinomas and is regarded as an important prognostic marker indicating poor patient survival 5. The aim of this study was to evaluate the expression of HER-2, estrogen (ER) and progesterone (PR) receptors in breast carcinoma and to compare it with other prognostic parameters such as histological type and grade, tumor size, patients' age, and lymph node metastases.

The prognosis of breast carcinomas is related to a large variety of clinical and pathological factors. It is well known that ER, PR and HER-2 represent the most acceptable factors for predicting prognosis response or resistance to treatment and the potential use of newer drugs 891011. The association between Her-2 gene amplification and poor prognosis was first determined in 1987 by Slamon et al 12. In the present study, HER-2 over expression was seen in 18.1% of Tunisian female patients' breast carcinomas. It has been reported that 10–34% of breast carcinomas over-express the HER-2 receptor. This characteristic is associated with more aggressive tumor behavior. The ErbB receptors themselves regulate estrogen-signaling pathways, either by directly phosphorylating the estrogen receptor, or by activating mitogen-activated protein kinases, which in turn enhance estrogen receptor signaling 1314; furthermore, previous studies of breast cancer cell lines have implicated growth factor in signaling repression of PR expression 15.

80 (51.6%) patients were less than 50 years old and 72 (46.4%) of them were between the ages of 30 and 50. In contrast to what is commonly known about a rising incidence of breast cancer with age, our results showed that 51.6% of the patients examined were young with an age below 50 years. The mean age of these patients was 51.5, and 46.4% of them were between the ages of 30 and 50. This age distribution is significantly younger than what is currently seen in Western and Arab countries 1617, and requires further careful examination to determine the nature of the predisposing factor(s). One possible explanation is that traditional marriages among first-degree relatives in Tunisia are very common, and, accordingly, hereditary factors could play a major role. Another factor could be the degree of obesity associated with a diet high in fat, carbohydrate, and protein, and lack of exercise, which have been prevalent in Tunisia the two last decades. The relative young mean age of our patients may be explained by the age distribution in our population or by risk factors that may be particular to our country.

Some authors 181920 have suggested that HER-2 overexpression is associated with young age; our study failed to reveal a significant relationship between HER-2 overxpression and patient's age (women older or younger than 50 years). This may be due to that our report is a small series.

In contrast, we found that there is a significant association between the nature of the tumors' expression of ER and the age of the patients. These results are in agreement with most reports in the literature which show an association between the expression of ER and age in breast carcinoma 18192122. However, other studies have found no association between the age and the degree of expression of ER by the tumor 23.

In our study, we did not find any significant association between the age of the patients and their tumor expression of PR. Similar findings were reported by many authors 242526. Other studies, however, have reported a higher tumor expression of PR in patients older than 59 years, as compared to those between 50 and 59 years 27.

Our results showed a tendency of HER-2 overexpression to be more associated with larger tumor size although this difference was not statistically significant. Similarly, the fraction of tumors larger than 5 cm tended to have higher rates of HER-2 overexpression than those below 5 cm in size (27% versus 15.3%). Several studies have found no association between Her-2 overexpression and tumor size 18282930. On the other hand, there was no statistically significant correlation between hormonal status and size. This result is in concordance with data reported in the literature 3132.

In our study, the most common histological subtypes were ductal-not otherwise specified (83.8%), followed by inflammatory carcinoma (5.1%), lobular carcinoma (3.8%) and mucinous carcinoma (3.8%). Inflammatory breast carcinoma is particularly common in Tunisia and the region of North Africa 24; this confirms the relatively high percentage of occurrence of this variety in our study. The highest percentage of HER-2 overexpression (50%) was seen in inflammatory carcinoma; this support the view that it known to have an aggressive clinical course, very often resulting in early recurrence and death. However, no statistically significant correlation was found between HER-2 overexpression and histological type which confirm the data of many reports 3334. In contrast, recent reports suggest that HER-2 overexpression is significantly more likely in infiltrating ductal carcinomas than in infiltrating lobular carcinomas 35. Our results show that there was no significant difference between ductal and lobular carcinoma regarding HER-2 overexpression. This could imply that, although lobular carcinoma is less common than ductal carcinoma, lobular carcinoma could be equally aggressive. On the other hand, there was no statistically significant correlation between hormonal status and histological type which has also been described in the literature 3132. In our study, some limitations should be considered when interpreting the results. This study was limited by relatively small numbers of non ductal subtypes: endocrine, medullary, metaplastic, and oncocytic carcinomas were three or fewer, resulting in estimates with wide confidence limits.

Most studies have correlated HER-2 overexpression with poor histological or nuclear grade of the primary tumor 91011282930363738, whereas others have not 3940.

Traina et al. 41 have demonstrated that only HER-2 (3+) and histopathologic grading 3 are significantly associated with overall survival. Similarly, our study showed that tumors with grade 3 were more often HER-2 negative.

In this study, we also found that lower grade (1–2) of the tumor was significantly related to the expression of ER and PR. Similar findings were reported by many studies 423132.

The prognostic importance of HER-2 has also been analyzed in the context of patient subgroups with or without lymph node involvement. Most of the studies that have examined the prognostic role of HER-2 in patients with positive lymph nodes have shown that HER-2 amplification/overexpression is associated with a worse outcome in either univariate or multivariate analysis 37414344. This finding was also confirmed in our study. A few studies, however, have not shown statistically significant correlation between HER-2 and lymph node status 182830.

Despite the great variation in levels of HER-2 positivity, nearly all investigators report a negative relationship between HER-2 status and steroid receptors levels 891011151828293036373841. Our results confirm this data. This inverse association has been linked to the fact that estrogens and its receptor are required to suppress HER-2 1314. This leads to lower or absent hormone receptors in women with HER-2 positive breast cancers. This is one of the reasons why women who express HER-2 may be resistant to tamoxifen 45.

Analysis of HER-2 status in breast carcinoma is important because it provides valuable prognostic, predictive and therapeutic information. In this study about 155 patients with infiltrating breast carcinomas, HER-2 overexpression was evaluated by immunohistochemistry and was observed in 28 cases (18.1%). Our results showed that HER-2 over-expression correlates with aggressiveness parameters such as high histological SBR grade, lymph node metastases and negative ER/PR status.

HER-2: Human epidermal growth factor receptor 2; ER: Estrogen receptor; PR: Progesterone receptor.

The authors declare that they have no competing interests.

LA designed the study, interpreted the results of HER-2, ER and PR expression, and drafted the manuscript. AK reviewed the histopathology of breast carcinoma, graded all the cases histologically and helped to draft the manuscript. HA participated in the sequence alignement and helped to draft the manuscript. SK prepared the histological slides and helped the immunoperoxydase stains on the cases. AD reviewed all clinical data and helped to draft the manuscript. MG participated in the design of the study and performed the statistical analysis. TSB conceived the study and participated in the design of the article and coordination and helped interpretation of the results of HER-2, ER and PR expression. All authors read and approved the final manuscript.