Apocrine carcinoma of the breast has recently been refined through gene expression profiling. Due to various pathological studies, we compared the results with the MDA-MB-453 breast cancer cell line, a proposed model for apocrine breast carcinoma. The MDA-MB-453 cell line is androgen receptor-positive and `triple-negative' in respect to estrogen receptor-α, progesterone receptor and the Her-2/neu protein expression. Cytogenetic analysis of the cell line revealed a hypertriploid clone characterized by extensive numerical and structural abnormalities including loss of the 9p.21 locus (P16-INK4a gene), also evidenced by the lack of p16(INK4A) protein expression in Western blot analysis and immunocytochemistry assays. Gains of chromosomes 7 and 17 without underlying EGFR, HER-2/neu, and TOP2A gene amplification were also observed. A mutation in the K-RAS gene (Gly13Asp GGC>GAC) was identified in the cell line, which was not observed in the six patient samples of apocrine breast carcinomas examined. Similarly, constitutive activation of the MAPK/ERK signaling pathway and deregulation of cell cycle proteins (p16-/pRb-/cyclin D1+ phenotype) with exceedingly high proliferation observed in the MDA-MB-453 cell line were not found in the tissue samples. In conclusion, the MDA-MB-453 cell line shares certain features with apocrine breast carcinoma but differs from patient tissues with regard to various significant characteristics, limiting the value of this cell line as a model for human apocrine breast carcinoma investigations. In contrast to the cell line, EGFR-positive apocrine carcinomas do not harbor K-RAS gene mutations, rendering these tumors amenable to targeted therapy with EGFR inhibitors.

Insulin-like growth factor-II mRNA-binding protein 3 (IMP3) is a member of the insulin-like growth factor-II signaling pathway, and has recently been described as a biomarker of basal-like breast carcinomas. This study explored IMP3 expression in adenoid cystic carcinomas of the breast, a special type of basal-like, triple-negative (estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2/neu protein negative) carcinoma and compared it with a group of apocrine carcinomas, which are an example of estrogen receptor/progesterone receptor negative, special type of breast carcinoma. Eighteen breast adenoid cystic carcinomas (16 primary and 2 corresponding metastases) and 18 apocrine carcinomas (16 invasive and 2 in situ) were evaluated for the expression of IMP3 protein using immunohistochemical method. A cut-off value for IMP3 positivity was set at 10%. Thirteen of 16 (81.3%) primary adenoid cystic carcinomas overexpressed IMP3 protein, predominantly in membranous distribution. The mean percentage of positive cells among primary adenoid cystic carcinomas was 50%. Both metastatic adenoid cystic carcinomas also strongly overexpressed IMP3 protein (70% and 80% of the tumor cells, respectively). In contrast, only 4 of 16 invasive apocrine carcinomas (25%) exhibited IMP3 positivity with significantly lower percentage of positive cells (27%, P<0.001). Two in-situ apocrine carcinomas were negative. Our results indicate that IMP3 may be an additional basal-type marker in breast carcinoma whose expression can be occasionally seen in other types of breast carcinomas such as apocrine type.

The current study was performed to determine the impact of polysomy 17 on the interpretation of HER2 testing of invasive breast carcinomas using fluorescent in situ hybridization methods. Current American Society of Clinical Oncology/College of American Pathologists guidelines define HER2‐positive tumors as those with >6 HER2 genes per nucleus or those with HER2/CEP17 (chromosome 17) ratio >2.2. These guidelines are potentially contradictory in tumors with polysomy of chromosome 17.

Background ER-α36 is a novel 36 kDa isoform of the full-length oestrogen receptor alpha (ER-α66). ER-α36 primarily localises to the cytoplasm and the plasma membrane, and responds to membrane-initiated oestrogen and antioestrogen signalling pathways. Aim To examine the expression of ER-α36 in apocrine and adenoid cystic carcinoma of the breast, both of which are consistently ER-α66 negative and currently lack effective targeted therapeutic options. Methods 19 pure apocrine carcinomas (17 invasive and two in-situ carcinomas) and 11 adenoid cystic carcinomas of the breast were evaluated for ER-α36 expression, along with expressions of ER-α66, progesterone receptor (PR) and androgen receptor (AR) using immunohistochemical methods. Results All pure apocrine carcinomas showed a characteristic steroid receptor expression profile (ER-α66 and PR negative, AR strongly positive). ER-α36 expression was detected in 18/19 pure apocrine carcinomas (94.7%, 95% CI 75.1 to 98.7) in predominantly membranous and cytoplasmic distribution. When positive, pure apocrine carcinomas uniformly (100% of cells) expressed ER-α36. All adenoid cystic carcinomas were uniformly negative for all three classic steroid receptors, but ER-α36 was detected in 8/11 cases (72.7%, 95% CI 42.8 to 90) with the similar sub-cellular pattern of expression as in the pure apocrine carcinomas. When positive, adenoid cystic carcinomas expressed ER-α36 in the majority of cells (average 76%). Conclusion ER-α36, a novel isoform of ER-α66, is frequently over-expressed in apocrine and adenoid cystic carcinomas of the breast. These results indicate a potential for a novel targeted treatment in these cancers.

Abstract:  Management of patients at high risk for hereditary breast cancer (HBC) must critically assess its phenotypic and genotypic heterogeneity, particularly evidenced by the varying spectra of cancer sites that are integral to the respective HBC syndromes. Targeted management must consider their biology, pathology, and molecular genetics, all in concert with their respective carcinogenic pathways, as they may differ significantly from one breast cancer syndrome to the next. A striking example of management differences pertains to BRCA1 and BRCA2 mutation‐positive breast cancers wherein those with BRCA1 mutations are frequently estrogen receptor (ER)‐negative in contrast to BRCA2 mutations which are more frequently ER‐positive; therein, significant differences exist with respect to anti‐estrogen therapy which will be more amenable to BRCA2 versus BRCA1 mutation carriers manifesting breast cancer. In turn, tumors that are negative for ER, PR, and Her2‐neu, often referred to as “triple negative” tumors, may also harbor a unique basal‐like gene expression profile and are characterized by poor prognosis wherein endocrine and/or Her2‐neu‐targeted therapies are not effective treatment options. A further confounder pertains to the lifetime risk for ovarian cancer, which differs strikingly between BRCA1 mutation carriers, who show a 40–60% lifetime risk, and their BRCA2 counterparts, who carry a lifetime risk of approximately 12–15% for ovarian cancer. It is clear that as we learn more about the biology and the molecular aspects of hereditary forms of breast cancer, it will be compelling for the clinician to integrate this knowledge with pharmacologic, radiologic, and surgical treatment options for these high‐risk patients.