Alterations of the Cell Cycle Regulators Cyclin D1, Cyclin A, p27, p21, p16, and pRb in Apocrine Metaplasia of the Breast

Abstract

G1/S transition defects have been a proposed requirement for tumor development. Apocrine metaplasia (APM) in the breast has been held as a sign of benignity. Yet, a number of studies have reported the presence of molecular abnormalities in some forms of APM suggesting a possible oncogenic potential for some of these lesions. We currently investigate the role of some of the cell cycle proteins, previously reported to be de-regulated in breast cancer, in an attempt to assess their significance in APM. Using immunohistochemistry, the expression of cyclin D1, cyclin A, p27, p21, p16, pRb and Ki-67 was examined in 93 cases of APM. The cases were divided into nonpapillary (NAPM) (30 cases) and papillary metaplasia (PAPM) (63 cases). PAPM was further subdivided into simple papillary (SPAPM) (29 cases), complex papillary (28 cases) and highly complex papillary (six cases). For statistical analysis, the last two groups were merged together (CPAPM). The results showed that increased histological complexity was associated with significant increase of proliferative capacity and alterations of the cell cycle control. The median Ki-67 index was 1.5% in SPAPM and 4.8% in the CPAPM. Also, alterations of the cell cycle regulators were significantly higher in the CPAPM than in the SPAPM. NAPM was generally similar to normal breast epithelium. Apocrine cells were negative for p16 while pRb was expressed in all cases. These findings suggest that in complex forms of APM, there is a considerable degree of cellular unrest. This may contribute to increased susceptibility to carcinogenesis.

Update on the molecular profile of the MDA-MB-453 cell line as a model for apocrine breast carcinoma studies

“…For ER-α, PR, AR, cyclin D1, p53, p63 and topoisomerase-IIα expression, only nuclear labeling was scored (24,25). For Her-2/neu and EGFR proteins, only membranous staining was considered positive.…”

Expression of C-KIT, CD24, CD44s, and COX2 in benign and non-invasive apocrine lesions of the breast

“…Wells et al [34] studied apocrine adenosis and suggested an association between apocrine adenosis, apocrine DIN, and invasive apocrine cancers based upon HER2 overexpression, nuclear p53 staining, and a high Ki-67-based proliferation index. El-Ayat G et al [7] studied Ki-67 and the cellcycle-regulating proteins cyclin D1 and pRb in apocrine metaplasia and found a significantly higher Ki-67 index and more indications of cell cycle deregulation in apocrine lesions with papillary/proliferative features than in apocrine lesions without papillary/proliferative features. The authors concluded that histologically more complex lesions are associated with significant increase of proliferative capacity and alterations of cell cycle control.…”

“…N total indicates the total number of lesions included in the study, but due to disappearance of the lesions on some slides, and limited number of slides available for staining, the number of stained lesions within each column may be smaller than N total a Not qualifying for DIN1c-3. Includes atypical apocrine metaplasia/ atypical apocrine hyperplasia and apocrine papillomas with DIN1b explored immunohistochemical markers related to tumor progression in proliferative and non-proliferative apocrine lesions [5][6][7]34]. Wells et al [34] studied apocrine adenosis and suggested an association between apocrine adenosis, apocrine DIN, and invasive apocrine cancers based upon HER2 overexpression, nuclear p53 staining, and a high Ki-67-based proliferation index.…”

“…More recently, studies using comparative genomic hybridization and loss of heterozygosity (LOH) have shown similar molecular alterations in benign and malignant apocrine lesions [2,4]. The notion that apocrine epithelium harbors genome instability, favoring malignant transformation, has also been supported by studies exploring biomarkers in apocrine lesions [5][6][7]. Benign apocrine lesions without atypia and non-invasive apocrine proliferations of the breast may show complete disappearance or a substantial reduction in the number of myoepithelial (ME) cells [8,9], a feature characteristic of but not exclusive to invasive cancer.…”

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

“…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].…”