Apocrine Cysts of the Breast

Abstract

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. Molecular & Cellular Proteomics 5:462-483, 2006.The human breast presents many benign lesions that involve both the glandular and stromal tissues. These include fibrocystic changes, benign breast tumors, and breast inflammatory disease (1). Fibrocystic changes affect more than 50% of women during their lifetime and are comprised of cystic dilation of ducts, apocrine metaplasia of ductal epithelium, fibrosis, adenosis, and intraductal epithelial proliferation (Ref. and references therein).Cysts are fluid-filled sacs that usually develop in the upper half of the breast and are most common in women between 30 and 50 years of age (3). They are also found in menopausal women on hormone replacement therapy. Cysts start as a microscopic dilation of the ductules (microcyst) but can enlarge and reach sizes of a couple of centimeters in diameter (macrocysts) causing pain and discomfort due to the tens...

FABP7 and HMGCS2 Are Novel Protein Markers for Apocrine Differentiation Categorizing Apocrine Carcinoma of the Breast

“…To determine if FABP7 and HMGCS2 antibodies are specific enough in terms of IHC staining to identify benign and malignant apocrine lesions [2], [16] we used a three-pronged strategy developed in our laboratory and described in detail elsewhere [23]: (i) analysis of potential cross-reactivity by 2D Western blotting (2D-WB), (ii) mass spectrometry validation of corresponding silver-stained protein spots superimposed with 2D-WB and (iii) IHC experiments with blocking of antibodies with a corresponding protein/epitope. This approach combines the intrinsic sensitivity and cellular resolution of IHC, with the specificity of 2D-WB and MS-based identification, and the overall protein analysis capability of gel-based proteomics [24].…”

“…With the aim to develop molecular criteria to reproducibly categorize IACs at the protein level we have undertaken a systematic proteomic analysis of well-defined set of apocrine carcinomas aimed at identifying biomarkers that may characterize and subtype these lesions to a greater detail, and to search for targets that may lead to the development of novel targeted therapies and chemoprevention strategies [2], [16], [17], [18], [19]. Accordingly, we have identified a number of apocrine protein markers that include 15-prostaglandin dehydrogenase (15-PGDH) and acyl-CoA synthetase medium-chain family member 1 (ACSM1) which together with a set of categorizing markers that are predominantly expressed (AR, CD24) or not expressed (bcl-2, GATA-3) by apocrine metaplastic lesions in benign breast lesions, were proven to be specific for both apocrine ductal carcinoma in situ (ADCIS) and IAC [2], [16], [17], [19], [20].…”

“…Accordingly, we have identified a number of apocrine protein markers that include 15-prostaglandin dehydrogenase (15-PGDH) and acyl-CoA synthetase medium-chain family member 1 (ACSM1) which together with a set of categorizing markers that are predominantly expressed (AR, CD24) or not expressed (bcl-2, GATA-3) by apocrine metaplastic lesions in benign breast lesions, were proven to be specific for both apocrine ductal carcinoma in situ (ADCIS) and IAC [2], [16], [17], [19], [20]. This apocrine signature has been shown to identify unambiguously 13 out of 14 ADCIS (92.9%) and 20 out of 33 (60.6%) IACs in a well characterized set of apocrine carcinomas [2] in which more than 90% of the tumor cells exhibited cytological features typical of apocrine cells [21].…”

Identification of specific reachable molecular targets in human breast cancer using a versatile ex vivo proteomic method

“…Our approach is along the line of the work of Celis et al [35,36], who analyzed the proteins found in the interstitial fluid that perfuses either the breast tumor microenvironment or the adipose tissue, and the work of Tammen et al [21], who analyzed the peptides and low molecular weight proteins extracted from tissues. Both methods identified also potentially "accessible" proteins (without chemical modifications) and were highly promising sources of biomarkers.…”

Adaptive contrast enhancement of two‐dimensional electrophoretic protein gel images facilitates visualization, orientation and alignment

“…It has been successfully used for protein analysis over more than three decades, and it is increasingly used in disease exploration [1][2][3][4]. Using 2-DE to map thousands of proteins presents the researcher with valuable information about a specific biological system.…”