Apoptosis, or programmed cell death, plays a major role not only in the formation and progression of cancer, but in the development of resistances to anticancer drugs as well [11
]. The genes p53 and bcl-2 play an important role in regulating the mechanisms of apoptosis [12
]. p53 is a tumor suppressor gene involved in the regulation of proliferative activity of human cells. Indeed, p53 serves a multifunctional role as a transcriptional regulator, genomic stabilizer, inhibitor of cell cycle progression, facilitator of apoptosis and also perhaps as inhibitor of angiogenesis [13
]. By all these mechanisms, wild type p53 slows proliferation, while mutations of these gene in cancer cells may result in higher proliferation rates, higher genetic instability, and resistance to apoptosis [14
]. Many studies have analyzed the prognostic impact of p53 alterations in breast cancer, and most of the studies have reported an association with worse outcome, either in node negative and node positive disease. However, others studies failed to demonstrate a significant association of p53 with poorer prognosis [8
]. In our series, p53 over-expression was found in 60.0% of breast cancers, a value in line with the reported values between 11 and 60% of p53 mutation in breast cancer by immunohistochemistry, but did not correlate to either bcl-2 expression or to disease-free and overall survival. It has been recently accepted that gene sequencing is the most appropriate method to study p53 status; indeed different types of mutated p53 oncogene exist that do not determine protein accumulation and are therefore not detected by immunohistochemistry [15
]. The discordance between our results and other studies may be partly due to the immunohistochemical technique used to detect p53 mutations and reflects the inconsistent data reported in literature for p53 mutation in breast cancer. The bcl-2 gene was initially identified in human bcls and its activity as apoptosis inhibitor, either drug and p53 induced, in cancer cells has been well demonstrated [7
]. As a consequence, the expression of bcl-2 in breast cancer cells should inhibit apoptosis and therefore relate to a worse outcome [1
]. On the contrary, the expression of bcl-2 in breast cancer has been found to be associated with favorable prognostic factors such as small tumor size, ER positivity, low nuclear grade and to predict a better outcome [7
]. These unexpected results may be explained by the fact that the ability of bcl-2 to inhibit apoptosis depends on the intracellular balance among a number of its family members, with other pro-apoptotic members such as Bax counteracting its action [7
]. Given its anti-apoptotic function, bcl-2 should be expected to correlate with worse prognosis. On the contrary, high levels of bcl-2 expression have been reported as associated to favorable tumor characteristics, such as low tumor size, low tumor grade, low proliferative activity and mainly with expression of ER and PgR [19
]. These associations account for the favorable prognostic impacts reported for bcl-2 expression on DFS and OS in breast cancer, either node negative and node positive, even if an independent prognostic role has been confirmed only in some series [20
]. Our data do not support the association of bcl-2 expression with other favorable prognostic factors and mainly with ERs expression, even if the percentages of bcl-2 and ERs expression in the study population are in line with the other series [22
]. On the other hand, data regarding outcome in our series are consistent with other studies; that bcl-2 expression doesn't correlate with better outcome, either for DFS and OS. Reasons for this unfavorable prognostic value of bcl-2 expression are not clear; possible explanations may include the pro-apoptotic activity of other members of the bcl-2 family, an inhibitory activity of bcl-2 on cell proliferation or the estrogen-inducibility of bcl-2 expression [10
]. In addition, data regarding outcome in our series are not consistent with other studies; that CK5/6 positivity correlates with better outcome, either for DFS and OS. Reasons for this favorable prognostic value of CK5/6 expression are not clear; possible explanations may include the small sample size, short-term follow-up period and no differences in survival rate between TNBC groups according to basal type.
In conclusion, paradoxically, CK5/6 positive TNBCs are higher DFS and OS than CK5/6 negative TNBCs. So, our study has some limitations in that CK5/6 can be used to classify TNBCs into at least two subtypes with differing survival rates. Also, the nuclear proliferation antigen, Ki-67, can be used to differentiate disease-free survival. But markers regulating cell cycle and cell death such as p53 and bcl-2 cannot be used to classify TNBCs into two subtypes with differing survival rates. However, because our study is small in size, there is no survival difference between TNBC groups according to basal type. So, more abundant patients' data will be needed to evaluate the pro-apoptotic activity of other members of the bcl-2 family's predictive role.