Inflammatory breast cancer (IBC) represents less than 10% of all breast cancers but is the most lethal form of the disease 1. Evolution of this distinct and aggressive form of locally-advanced breast cancer depends on the type of neo-adjuvant chemotherapy but is overall poor 2. IBC, classified T4d (stage IIIB) according to the TNM classification of the American Joint Committee of Cancer 5, is generally a rapidly growing tumor associated with cutaneous erythema and edema 234. The inflammatory aspect is associated with highly angiogenic and angio-invasive properties and with the presence of dermal lymphatic emboli 5. The high metastatic potential of IBCs suggests a high propensity of the tumor cells to migrate.

IBCs in Tunisia are characterized by a higher frequency and a higher aggressiveness than in European countries 678. However, we did not observe any difference between Tunisian and French IBCs in the expression of five representative proteins (E-cadherin, Estrogen receptor (ER), MIB1, MUC1 and ERBB2) 910.

In non-IBCs the five molecular subtypes (luminal A and B, basal, ERBB2-overexpressing and normal-like) are associated with different features, including response to chemotherapy and clinical outcome 11. Basal and ERBB2 subtypes have the worst prognosis, followed by luminal B subtype. The proportion of these subtypes has been determined by gene expression profiling in European IBC. Around half the cases are of basal and ERBB2 subtypes.

The subtypes defined by gene expression analysis have also been defined at the protein level using various markers. A panel of antibodies (directed against ER, ERBB2, EGFR, basal cytokeratin CK5/6 and/or KIT) identifies basal tumors with high specifity 12. Other markers such as P-cadherin, CK14, P53, CAV1, PR, MIB1 and moesin also identify basal tumors 13141516. Reciprocally, the expression of ER and ERBB2 exclude basal tumors.

The high frequency of the two subtypes associated with poor prognosis, basal and ERBB2, explains only in part the fatal evolution of IBC. In IBCs, the luminal cases also have a poor prognosis. Only a factor common to all subtypes could explain IBC poor evolution.

In breast cancer, P-cadherin is associated with enhanced cell invasion, tumor aggressiveness, motility 17 and with a poor prognosis 1819. P-cadherin mRNA is essentially expressed in basal carcinomas 2021.

The aims of this study were to determine the importance of breast carcinoma subtypes in IBC and to identify a factor that could explain the poor prognosis of IBC. We show that this factor could be associated with P-cadherin expression.

The identification of a specific IBC profile could improve the diagnosis, treatment and evolution of this aggressive form of locally-advanced breast cancer with high metastatic potential. In Tunisia, IBCs are frequent and have a worse prognosis than in European countries. However, in a previous study, we did not observe any difference in protein expression between IBCs from France and Tunisia 10. Five major molecular subtypes have been defined by gene expression profiling 112029. Basal and ERBB2 subtypes represent each about 20% of cases. These subtypes could also be recognized at the protein level, with a very good correlation with RNA analyses. IHC-defined subtypes also show differences in prognosis in non-IBCs: basal and ERBB2-overexpressing subtypes are associated with poor prognosis. To better understand the specificity and the poor prognostic of IBCs in general and Tunisian IBCs in particular, we studied by IHC on TMA the expression of proteins commonly used as markers for molecular subtypes.

We studied several markers but eventually used a simple operational definition based on ER and ERBB2 expression. The basal subtype was defined as negative for both ER and ERBB2. In non-IBCs basal and ERBB2 subtypes represent around 40% of cases. We compared only infiltrating ductal cases. We found differences in the proportion of subtypes in Tunisian IBCs. Basal and ERBB2 subtypes made up each about one-third of the cases. Overall, these data and those of the literature show an over-representation of basal and ERBB2 cases in IBCs as compared with non-IBCs 3031.

However, the high proportion of basal and ERBB2 subtypes is not sufficient per se to explain IBC prognosis. Only a factor common to all subtypes could explain IBC poor evolution. Surprisingly, we found that luminal IBCs express basal markers such as P-cadherin. Indeed, P-cadherin expression was not only higher in basal IBCs than in basal non-IBCs (95%/69%) but also higher in the IBC luminal cases (82%/42%). The logistic regression analysis showed that P-cadherin was the most representative marker of IBC.

P-cadherin is one of the most specific markers of myoepithelial cells and is associated with basal subtype. The frequency of P-cadherin IHC expression varies from 20% in initial works 32 to 40% in more recent series33. This percentage exceeds that of basal tumors suggesting that P-cadherin could also be expressed in non-basal cases. P-cadherin expression in breast cancer correlates with high grade, lack of ER/PR expression, increased tumor aggressiveness, high proliferation rate, and poor survival. P-cadherin is associated with MIB1, EGFR, ERBB2, P53 and CK5/6 expression 23. This expression may be due to hypomethylation of the gene promoter 18. Deregulated P-cadherin expression may alter epithelial cell behavior thereby contributing to a more aggressive tumor cell phenotype and poor survival 34. P-cadherin has pro-invasive activity in the MCF-7/AZ luminal breast cancer cell line, through interaction with signaling proteins bound to its juxtamembrane domain. ICI182,780, which blocks ER, induces increased expression of P-cadherin, which is associated with in vitro invasion35. Overexpressed P-cadherin increases motility of pancreatic cancer cells by interacting with p120ctn and subsequent activation of RHO GTPases 36. Activation of RHO GTPases has been observed in IBC. Overexpression of RHOC is associated with the loss of expression of WISP3 3738, which acts as a tumor suppressor. RHOC is overexpressed in over 90% of IBCs vs 36% of non-IBCs. RHOC activity requires NFκB stimulation 39. P-cadherin transgenic mice do not develop mammary tumors spontaneously. When mammary tumors are induced in the P-cadherin transgenic mice through breeding with the MMTV/neu transgenic mouse, the tumors do not express P-cadherin. This indicates that P-cadherin is not per se an oncogene 34.

Expression of P-cadherin in luminal IBC may indicate that the tumor cells derive from a stem/basal cell that has acquired ER expression and a luminal phenotype but retained some basal features. This suggests that IBC derives from a basal cell and progress along a specific oncogenic pathway allowing partial differentiation. This origin may be associated with specific IBC features and aggressiveness even in luminal cases. Although it may contribute, P-cadherin expression may be a sign of but not the reason for this aggressiveness.

The author(s) declare that they have no competing interests.

ABH and JJ carried out the design of the study and the analysis and interpretation of the data and drafted the manuscript. JJ, ECJ and KM are the pathologists responsible for the diagnosis, dissection of the tumor material and interpretation of the immunohistochemical staining. ISL provided and analyzed clinical data. BE carried out the statistical analysis. PV, SBA, LX and FB were involved in the design. DB participated in the draft of the manuscript and the analysis and interpretation of results. All authors read and approved the final manuscript.

CK: Cytokeratin; ER: Estrogen receptor; GTPase: Guanosine triphosphate; IBC: Inflammatory breast cancer; IHC: Immunohistochemistry; MMTV: Mouse mammary tumor virus; NF-kappa B: Nuclear factor; PR: Progesterone receptor; TMA: Tissue microarrays.