This article reviews the current status of hormone receptor evaluation in and out of Japan, and introduces the proposed working protocol of the task force for Adequate immunohistochemical evaluation in routine practice for breast cancer by the Japanese Breast Cancer Society. Understanding the principles and the developmental process of immunohistochemistry helps us to utilize a scoring system adequately. Methodologies of hormone receptor examination and immunohistochemical procedures are briefly introduced. Each scoring system is based on different principles. The proposed working protocol takes into account the reproducibility of results among observers, institutions and staining procedures, which is justified based on the current situation in Japan. Future directions for the standardization of immunohistochemical hormone receptor evaluation are also described.

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Cells from breast cancers lacking hormone receptors (estrogen receptor[I n mammary glands, estrogen plays a major role in duct elongation and branching, and accelerates the proliferation of epithelial cells, whereas progesterone contributes to lobule formation. In non-neoplastic mammary glands, estradiol is thought to act as a paracrine mitogen because no co expression of estrogen receptor (ER)α and cell proliferation markers (Ki-67 or proliferating cell nuclear antigen [PCNA]) has been detected. A recent study by Dimitrakakis et al. demonstrated that ERα and the estrogen-induced proteins MYC, cyclin D1, and stromal cell-derived factor-1 are co-expressed within the nuclei of monkey mammary glands.(1) Responsiveness to estrogen is retained after carcinogenesis in approximately 70% of all breast cancers. Two different mechanisms have been proposed to explain the mitogenic effects of estrogens in breast cancer tissue:(2) genomic action via estrogen-responsive elements located in the promoter regions of c-fos (3) and c-myc, (4) which have mitogenic activity involving G 1 -phase progression; or indirect action on cyclin D1 gene transcription.(5) Induction of cyclin D1 is strictly regulated in a hormone-dependent manner, and cAMP response elements in the promoter region of the cyclin D1 gene require the activation function (AF)-1 and AF-2 domains of ERα. Other non-genomic actions of estrogen via mitogen-activated protein kinase (MAPK)-external signal-regulated kinase (ERK) and phosphatidylinositol 3 kinase (PI3K)-Akt have also been proposed. (2) Human epidermal growth factor receptor (HER)2 is a tyrosine kinase receptor, the biological and clinical role of which has been investigated thoroughly in breast cancer. No specific ligands for HER2 have been found, but dimers containing HER2 (e.g. homodimers of HER2 or HER2-HER3 heterodimers) can strongly activate intracellular signaling for cell proliferation, cell survival, motility, and adhesion.(6) Two major signaling pathways for the HER family are the Raf-MEK-ERK pathway and the PI3K-phosphoinositide-dependent kinase (PDK1)-Akt pathway. These signal-transduction pathways regulate the expression of genes in many ways to promote cell-cycle progression by inhibition of p27 (8,9) and activation of cyclin D1, (10) and to inhibit apoptosis by phosphorylation of Bad and caspase 9. (11) Thus, the mechanisms of cell proliferation have been thoroughly investigated for hormone receptor-positive and HER2-positive breast cancers. In contrast, in breast cancers lacking hormone receptors and HER2, the signaling pathways responsible for cell proliferation are not well characterized. Cell proliferation in triplenegative breast cancer cells must be regulated in an ER or HER2 signaling-independent manner. The present study was conducted to examine the phosphorylation of HER2, ERK1/2, and Akt kinases, which are key kinases in two major signaling pathways, in order to obtain data to support further investigations into the molecular events contributing to cell proliferation. Materials and Me...

The purpose of the present study is to identify genes that contribute to cell proliferation or differentiation of breast cancers independent of signalling through the oestrogen receptor (ER) or human epidermal growth factor receptor 2 (HER2). An oligonucleotide microarray assayed 40 tumour samples from ER(+)/HER2(−), ER(+)/HER2(+), ER(−)/HER2(+), and ER(−)/HER2(−) breast cancer tissues. Quantitative reverse transcriptase PCR detected overexpression of a cell cycle-related transcription factor, E2F-5, in ER-negative breast cancers, and fluorescence in situ hybridisation detected gene amplification of E2F-5 in 5 out of 57 (8.8%) breast cancer samples. No point mutations were found in the DNA-binding or DNA-dimerisation domain of E2F-5. Immunohistochemically, E2F-5-positive cancers correlated with a higher Ki-67 labelling index (59.5%, P =0.001) and higher histological grades ( P =0.049). E2F-5-positive cancers were found more frequently in ER(−)/progesterone receptor (PgR)(−)/HER2(−) cancer samples (51.9%, P =0.0049) and in breast cancer samples exhibiting a basal phenotype (56.0%, P =0.0012). Disease-free survival in node-negative patients with E2F-5-positive cancers was shorter than for patients with E2F-5-negative cancers. In conclusion, we identify, for the first time, a population of breast cancer cells that overexpress the cell cycle-related transcription factor, E2F-5. This E2F-5-positive breast cancer subtype was associated with an ER(−)/PgR(−)/HER2(−) status, a basal phenotype, and a worse clinical outcome.

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