Loss of heterozygosity and allelic imbalance in apocrine metaplasia of the breast: microdissection microsatellite analysis

Selim, Abdel-Ghani A.; Ryan, Andy; Elayat, Ghada; Wells, Clive

doi:10.1002/path.1043

Cited by 27 publications

(20 citation statements)

References 12 publications

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“…Up to one-third of the women aged 30 -50 years have cysts in their breasts (3), and both their frequency and their proposed association with an increased risk of breast cancer have underpinned the importance of investigating these lesions at the molecular level (53,89). In particular, apocrine changes, which span from benign metaplasias to atypical apocrine hyperplasia (12,53), have attracted much attention because apocrine epithelia may be a precursor in malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

Apocrine Cysts of the Breast

Celis

Gromov

Moreira

et al. 2006

Molecular & Cellular Proteomics

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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...

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Section: Discussionmentioning

confidence: 99%

Apocrine Cysts of the Breast

Celis

Gromov

Moreira

et al. 2006

Molecular & Cellular Proteomics

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“…Based on morphological, immunohistochemical, and molecular findings, CCL, ADH, and well-differentiated DCIS would be unlikely candidates. Although apocrine change has long been considered a metaplastic process in breast tissues, usually associated with ageing, this concept has come into question with the application of molecular findings [2,17,[71][72][73]. At least a subset of lesions with apocrine morphology show molecular changes, including LOH/allelic imbalance at 1p (MYCL1), 11q (INT2), 13q, 16q and 17q [71,72], and recurrent chromosomal changes as defined by CGH, including loss of 1p, 2p, 10q, 16q, 17q and 22q, and gain of 1p, 2q and 13q [17].…”

Section: Hyperplasias and Columnar Cell Changementioning

confidence: 99%

Molecular evolution of breast cancer

Simpson

Reis‐Filho

Gale

et al. 2005

The Journal of Pathology

453

378

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Molecular analysis of invasive breast cancer and its precursors has furthered our understanding of breast cancer progression. In the past few years, new multi-step pathways of breast cancer progression have been delineated through genotypic-phenotypic correlations. Nuclear grade, more than any other pathological feature, is strongly associated with the number and pattern of molecular genetic abnormalities in breast cancer cells. Thus, there are two distinct major pathways to the evolution of low-and high-grade invasive carcinomas: whilst the former consistently show oestrogen receptor (ER) and progesterone receptor (PgR) positivity and 16q loss, the latter are usually ER/PgR-negative and show Her-2 overexpression/amplification and complex karyotypes. The boundaries between the evolutionary pathways of well-differentiated/low-grade ductal and lobular carcinomas have been blurred, with changes in E-cadherin expression being one of the few distinguishing features between the two. In addition, lesions long thought to be precursors of breast carcinomas, such as hyperplasia of usual type, are currently considered mere risk indicators, whilst columnar cell lesions are now implicated as non-obligate precursors of atypical ductal hyperplasia (ADH) and well-differentiated ductal carcinoma in situ (DCIS). However, only through the combination of comprehensive morphological analysis and cutting-edge molecular tools can this knowledge be translated into clinical practice and patient management.

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“…The authors concluded that histologically more complex lesions are associated with significant increase of proliferative capacity and alterations of cell cycle control. Furthermore, comparative genomic hybridization has shown a similar pattern of molecular alterations in benign and malignant apocrine lesions [2,4], implying that some apocrine lesions without atypia might also be clonally derived. This is supported by findings of LOH and allelic imbalance in apocrine metaplasia [4].…”

Section: Discussionmentioning

confidence: 94%

“…Furthermore, comparative genomic hybridization has shown a similar pattern of molecular alterations in benign and malignant apocrine lesions [2,4], implying that some apocrine lesions without atypia might also be clonally derived. This is supported by findings of LOH and allelic imbalance in apocrine metaplasia [4]. Our finding of an almost complete loss of C-KIT expression in benign apocrine lesions is consistent with an earlier report which suggests that C-KIT expression, regardless of cell type, is an indicator of potential for neoplastic transformation.…”

Section: Discussionmentioning

confidence: 94%

“…This has been supported by classical histopathological studies comparing the frequency of AM in breast cancer and non-breast cancer patients [1]. 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].…”

Section: Introductionmentioning

confidence: 92%

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

et al. 2016

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Benign apocrine metaplasia (AM) of the adult breast is a very common, but enigmatic lesion. It has been speculated that AM might be a precursor of malignancy or an indicator of a susceptibility of the breast tissue to develop neoplasia, mainly based on comparing the frequency of AM in breast cancer and non-breast cancer patients [1]. Studies using comparative genomic hybridization have supported this by showing similar molecular alterations in benign and malignant apocrine lesions [2]. Few studies, however, have compared expression of biomarkers involved in tumor progression in AM and progressively more advanced atypical apocrine lesions. The expression of C-KIT, COX2, CD24, and CD44s was evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded material of 9 AM, 20 apocrine ductal intraepithelial neoplasia (DIN1c-3) and 40 atypical apocrine lesions (not qualifying for DIN1c-3) and compared to expression of the same biomarkers in adjacent normal ductal epithelium. Of the 66 apocrine lesions, 62 (94 %) did not express C-KIT compared to 4/63 (6 %) of the normal glands (Fisher's exact, p < 0.001). COX2 was expressed in a significantly higher proportion of apocrine lesions than of normal glands (49 vs. 14 %, p < 0.001), and the number of apocrine lesions positive for CD24 was found to be higher with increasing aggressiveness of the lesions (Spearman, p < 0.001). In conclusion, benign and non-invasive proliferative apocrine lesions of the breast display immuno-phenotypical characteristics previously ascribed mainly to malignant transformation. This could lend support to the theory that AM is an early step towards malignant transformation, albeit associated with slow progression to carcinoma.

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Loss of heterozygosity and allelic imbalance in apocrine metaplasia of the breast: microdissection microsatellite analysis

Cited by 27 publications

References 12 publications

Apocrine Cysts of the Breast

Apocrine Cysts of the Breast

Molecular evolution of breast cancer

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

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