15-prostaglandin dehydrogenase expression alone or in combination with ACSM1 defines a subgroup of the apocrine molecular subtype of breast carcinoma

Established histopathological criteria divide invasive breast carcinomas into defined groups. Ductal of no specific type and lobular are the two major subtypes accounting for around 75 and 15% of all cases, respectively. The remaining 10% include rarer types such as tubular, cribriform, mucinous, papillary, medullary, metaplastic, and apocrine breast carcinomas. Molecular profiling technologies, on the other hand, subdivide breast tumors into five subtypes, basal-like, luminal A, luminal B, normal breast tissue-like, and ERBB2-positive, that have different prognostic characteristics. An additional subclass termed "molecular apocrine" has recently been described, but these lesions did not exhibit all the histopathological features of classical invasive apocrine carcinomas (IACs). IACs make up 0.5-3% of the invasive ductal carcinomas, and despite the fact that they are morphologically distinct from other breast lesions, there are presently no standard molecular criteria available for their diagnosis and as a result no precise information as to their prognosis. Toward this goal our laboratories have embarked in a systematic proteomics endeavor aimed at identifying biomarkers that may characterize and subtype these lesions as well as targets that may lead to the development of novel targeted therapies and chemoprevention strategies. By comparing the protein expression profiles of apocrine macrocysts and non-malignant breast epithelial tissue we have previously reported the identification of a few proteins that are specifically expressed by benign apocrine lesions as well as by the few IACs that were available to us at the time. Here we reiterate our strategy to reveal apocrine cell markers and present novel data, based on the analysis of a considerably larger number of samples, establishing that IACs correspond to a distinct molecular subtype of breast carcinomas characterized by the expression of 15-prostaglandin dehydrogenase alone or in combination with a novel form of acyl-CoA synthetase medium-chain family member 1 (ACSM1). Moreover we show that 15-prostaglandin dehydrogenase is not expressed by other breast cancer types as determined by gel-based proteomics and immunohistochemistry analysis and that antibodies against this protein can identify IACs in an unbiased manner in a large breast cancer tissue microarray making them potentially useful as a diagnostic aid.     

Apocrine cysts of the breast: biomarkers, origin, enlargement, and relation with cancer phenotype

Up to one-third of women aged 30-50 years have cysts in their breasts and are presumed to be at increased risk of developing breast cancer. Here we present an extensive proteomic and immunohistochemistry (IHC) study of breast apocrine cystic lesions aimed at generating specific biomarkers and elucidating the relationship, if existent, of apocrine cysts with cancer phenotype. To this end we compared the expression profiles of apocrine macrocysts obtained from mastectomies from high risk cancer patients with those of cancerous and non-malignant mammary tissue biopsies collected from the same patients. We identified two biomarkers, 15-hydroxyprostaglandin dehydrogenase and 3-hydroxymethylglutaryl-CoA reductase, that were expressed specifically by apocrine type I cysts as well as by apocrine metaplastic cells in type II microcysts, terminal ducts, and intraductal papillary lesions. No expression of these markers was observed in non-malignant terminal ductal lobular units, type II flat cysts, stroma cells, or fat tissue as judged by IHC analysis of matched non-malignant tissue samples collected from 93 high risk patients enrolled in our cancer program. IHC analysis of the corresponding 93 primary tumors indicated that most apocrine changes have little intrinsic malignant potential, although some may progress to invasive apocrine cancer. None of the apocrine lesions examined, however, seemed to be a precursor of invasive ductal carcinomas, which accounted for 81% of the tumors analyzed. Our studies also provided some insight into the origin, development, and enlargement of apocrine cysts in mammary tissue. The successful identification of differentially expressed proteins that characterize specific steps in the progression from early benign lesions to apocrine cancer opens a window of opportunity for designing and testing new approaches for pharmacological intervention, not only in a therapeutic setting but also for chemoprevention, to inhibit cyst development as both 15-hydroxyprostaglandin dehydrogenase and 3-hydroxymethylglutaryl-CoA reductase are currently being targeted for chemoprevention strategies in various malignancies.     

Fine needle aspiration cytology of apocrine carcinoma of the breast. Review of cases in a three-year period

OBJECTIVE: To describe the fine needle aspiration cytology findings of apocrine carcinoma of breast and correlate them with the histologic appearance. STUDY DESIGN: The author reviewed the fine needle aspiration cytology findings of two cases of pure apocrine carcinoma of the breast in the files of Pamela Youde Nethersole Eastern Hospital during a three-year period, 1998-2000. RESULTS: The cytologic findings in both cases were similar. The smears were of moderate to high cellularity, consisting of predominantly dispersed or loosely cohesive tumor cells in a focally granular background. The carcinoma cells contained abundant, dense to granular cytoplasm; round or oval and sometimes eccentrically located nuclei; a smooth nuclear outline; evenly dispersed chromatin; and solitary macronucleoli. The cell borders were mostly discrete. In contrast to benign apocrine cells, the malignant cells showed nuclear overlapping, more frequent nuclear pleomorphism, increased nuclear/cytoplasmic ratios and occasional mitotic figures. Histologic examination of the excised specimens showed extensive, solid apocrine carcinoma in situ with focal stromal invasion. CONCLUSION: Apocrine carcinoma, a subtype of breast carcinoma characterized mainly by its cytologic features, needs to be distinguished from benign apocrine lesions or other eosinophilic and granular cell tumors of the breast. Recognition of the subtle cytologic differences renders a definitive preoperative diagnosis possible.     

DNA nuclear content of apocrine cells in fibrocystic mastopathy and breast cancer

The DNA nuclear content of apocrine cells was studied in 5 cases of fibrocystic disease, 3 cases of invasive duct carcinoma and 3 cases of invasive lobular carcinoma. Both diploid and aneuploid values were found in each group. The possible significance of apocrine change in breast lesions is discussed.     

Histiocytoid change in breast carcinoma: a report of 3 cases with an unusual cytomorphologic pattern of apocrine change

BACKGROUND: Breast carcinomas composed predominantly or exclusively of cells with foamy and/or granular cytoplasm have been termed histiocytoid breast carcinoma. CASES: Three cases of HBC had fine needle aspirates that were moderately cellular and composed of cells with abundant foamy and/or granular cytoplasm, arranged in loosely cohesive groups and dispersed singly. The cells showed subtle cytologic atypia, including nuclear hyperchromasia and slightly irregular nuclear outlines. Definitive cytologic diagnosis was not possible in the 3 cases, and they were reported as "suspicious for malignancy." Core biopsies of 2 cases showed a typical Indian file pattern of invasive lobular carcinoma, while the third case was composed of sheets of discohesive histiocytoid cells admixed with a prominent lymphoid infiltrate. All 3 cases were E-cadherin negative, confirming their lobular nature. CONCLUSION: HBC represents an unusual morphologic pattern of apocrine change that may be seen in lobular and ductal breast carcinomas. Recognition of these lesions is vital in that they may be mistaken for a variety of other entities composed of foamy/granular cells; some of those entities have vastly different implications for treatment and prognosis.     

15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer

Prostaglandin E2 (PGE2) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE2 stem from relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas. Consistent with these findings, we observe diminished 15-Pgdh expression in ApcMin+/- mouse adenomas. Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE2 metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue. In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression.     

Diagnostic pitfalls in fine needle aspiration cytology of atypical apocrine metaplasia in a breast lesion. A case report

BACKGROUND: Apocrine metaplastic cells are frequently encountered in fine needle aspirates of breast lesions. Atypical apocrine metaplastic cells with signet ring features can also occur, and their presence may present a diagnostic dilemma in the differentiation of benign versus malignant lesions. CASE: A fine needle aspirate of a 2.5 x 1.0-cm, subareolar mass in a 47-year-old female showed atypical cells with signet ring morphology. Also present were clusters of cells that were enlarged and showed nuclear atypia, prominent nucleoli and cytoplasmic granules. Papillary cohesive clusters of ductal cells were also identified. The fine needle aspiration diagnosis was mucinous carcinoma. The nodule was excised, and the histologic diagnosis was sclerosing ductal papilloma with atypical apocrine metaplasia. CONCLUSION: Atypical apocrine cells can be misinterpreted as mucinous carcinoma or usual duct adenocarcinoma on fine needle aspiration cytology. We present clues that may help in rendering the correct interpretation.     

乳腺癌及良性乳腺组织p185和p16蛋白表达的免疫组织化学研究

应用免疫组化S P法检测了 37例良性乳腺组织 (非上皮增生组 17例、上皮增生组 2 0例 )和 5 9例乳腺癌组织中癌基因蛋白 p185和抑癌基因 p16蛋白的表达状况。结果显示非上皮增生组、上皮增生组和癌的p185阳性率分别为 0 %、15 %和 47%(p <0 0 1) ;p16阳性率分别为 41%、30 %和 34%。p185和p16的表达无明显相关性。乳腺癌早期的 p185过表达和p16失表达率高于浸润性导管癌。两者的阳性率均随组织学级别的增高和瘤体的增大而呈上升趋势 ,但 p >0 0 5。淋巴结转移组的p185阳性率 ( 6 4%)明显高于无淋巴结转移者 ( 32 %) ,p <0 0 5。表明 p185过表达和p16失表达在乳腺癌的发生发展中各自发挥独立的作用。p185是乳腺癌重要的肿瘤标志物。