Immunohistochemical Analysis of Ki-67, p53, p21, and p27 in Benign and Malignant Apocrine Lesions of the Breast: Its Correlation to Histologic Findings in 43 Cases

Moriya, Takuya; Sakamoto, Kazuhiro; Sasano, Hironobu; Kawanaka, Miwa; Sonoo, Hiroshi; Manabe, Toshiaki; Ito, Jishu

doi:10.1038/modpathol.3880004

Cited by 67 publications

(51 citation statements)

References 11 publications

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“…Study of prostate carcinoma also showed variable degrees of reduction in p27 KIP1 staining was frequently observed in the prostatic intraepithelial neoplasia adjacent to invasive carcinoma 66 . Studies of breast cancer also have similar results; p27 KIP1 protein is reduced in premalignant and non-invasive malignant lesions, including ductal carcinoma in situ of the breast [68][69][70][71] . In addition, a comparison of p27 KIP1 protein levels in primary colon carcinoma and metastatic tumour demonstrated a reduction of p27 KIP1 staining in the metastatic tumour 72,73 .…”

Section: P27supporting

confidence: 55%

Cyclin D1 and P27KIP1: The Gatekeepers of Dysplasia

Love¹

2018

J Immunological Sci

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There is increasing evidence suggesting that cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CDIs) either are themselves targets for genetic change in cancer or are disrupted secondarily by other oncogenic events. Cyclin D1 and p27 KIP1 are two important regulators at the G1/S checkpoint. Cyclin D1 is an oncogene of cell cycle regulation with positive effect. Normally, cyclin D1 at G1 is constant or at a very low level and its excessive expression may be associated with the disordered proliferation of cells leading to malignant change. On the other hand, p27KIP1 is an antioncogene for cell cycle regulation, which functions as a negative regulator. Under the regulation of TGF-β, p27KIP1 inhibits the activity of oncogenes and controls the transition of the G1/S phase mainly by the interaction with CDK and CDK-Cyclin in order to inhibit cell proliferation and give cells opportunities to repair DNA. In addition, p27KIP1 not only acts as CDK inhibitor, but also promotes cell differentiation and induces the apoptosis of cells. In this article we review studies that have explored the effects of cyclin D1 and P27 KIP1 on cancer progression and dysplasia with a specific focus on oral dysplasia and oral squamous cell carcinoma (OSCC). We also aim to shed some light on the different means of evaluating the interaction between Cyclin D1 and P27 KIP1 as well as the immunohistochemical reactions associated with different forms of cyclin D1. CELL CYCLEThe cell cycle is the series of events that are required to create two daughter cells from a progenitor cell. The cell division cycle consists of four phases, i.e. G1, S, G2, and M. A cell that is not in the cell cycle is in a quiescent state named G0. G1 is the interval before DNA replication, S is the DNA replication phase, G2 is the interval after DNA replication, M is the mitotic phase. Progression through the cell cycle is governed by a family of cyclin-dependent kinases (CDKs), the activity of which is regulated by phosphorylation The orderly progression through the different phases is assured by proteins that regulate critical checkpoints. Several checkpoints have been identified such as the late G1 phase restriction point, the G1/S phase transition, and the G2/M phase transition. These checkpoints normally verify that the preceding events have been completed before progressing to the next monitor completion of DNA replication and produce signals that interrupt the cell cycle in the event of an error or damage to the genome. Abnormal functioning of checkpoints, such as incapacity in detecting damaged DNA, may play a significant role in tumour progression by permitting cells to progress through the cell cycle with damaged or abnormal DNA 4 .

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Section: P27supporting

confidence: 55%

Cyclin D1 and P27KIP1: The Gatekeepers of Dysplasia

Love¹

2018

J Immunological Sci

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“…5C) (17) and exhibited a low proliferation index as judged by staining with the Ki67 antibody ( Fig. 5D) (77).…”

Section: Characterization Of the Proteome Profile Of Apocrinementioning

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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“…Apocrine micro-and macrocysts do not express estrogen receptor alpha (ER-alpha) and progesterone receptor (PR) [55][56][57], but are positive for the androgen receptor (AR) and Her-2 Neu [13,20]. In addition, these lesions exhibit a low proliferative index as determined by staining with the Ki67 antibody [20,56].…”

Section: Apocrine Differentiation Of Breast Epithelial Cellsmentioning

confidence: 99%

“…In addition, these lesions exhibit a low proliferative index as determined by staining with the Ki67 antibody [20,56].…”

Section: Apocrine Differentiation Of Breast Epithelial Cellsmentioning

confidence: 99%

Molecular pathology of breast apocrine carcinomas: A protein expression signature specific for benign apocrine metaplasia

et al. 2006

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Breast cancer is a heterogeneous disease that encompasses a wide range of histopathological types including: invasive ductal carcinoma, lobular carcinoma, medullary carcinoma, mucinous carcinoma, tubular carcinoma, and apocrine carcinoma among others. Pure apocrine carcinomas represent about 0.5% of all invasive breast cancers according to the Danish Breast Cancer Cooperative Group Registry, and despite the fact that they are morphologically distinct from other breast lesions, there are at present no standard molecular criteria available for their diagnosis. In addition, the relationship between benign apocrine changes and breast carcinoma is unclear and has been a matter of discussion for many years. Recent proteome expression profiling studies of breast apocrine macrocysts, normal breast tissue, and breast tumours have identified specific apocrine biomarkers [15-hydroxyprostaglandin dehydrogenase (15-PGDH) and hydroxymethylglutaryl coenzyme A reductase (HMG-CoA reductase)] present in early and advanced apocrine lesions. These biomarkers in combination with proteins found to be characteristically upregulated in pure apocrine carcinomas (psoriasin, S100A9, and p53) provide a protein expression signature distinctive for benign apocrine metaplasias and apocrine cystic lesions. These studies have also presented compelling evidence for a direct link, through the expression of the prostaglandin degrading enzyme 15-PGDH, between early apocrine lesions and pure apocrine carcinomas. Moreover, specific antibodies against the components of the expression signature have identified precursor lesions in the linear histological progression to apocrine carcinoma. Finally, the identification of proteins that characterize the early stages of mammary apocrine differentiation such as 15-PGDH, HMG-CoA reductase, and cyclooxygenase 2 (COX-2) has opened a window of opportunity for pharmacological intervention, not only in a therapeutic manner but also in a chemopreventive setting. Here we review published and recent results in the context of the current state of research on breast apocrine cancer.

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Immunohistochemical Analysis of Ki-67, p53, p21, and p27 in Benign and Malignant Apocrine Lesions of the Breast: Its Correlation to Histologic Findings in 43 Cases

Cited by 67 publications

References 11 publications

Cyclin D1 and P27KIP1: The Gatekeepers of Dysplasia

Cyclin D1 and P27KIP1: The Gatekeepers of Dysplasia

Apocrine Cysts of the Breast

Molecular pathology of breast apocrine carcinomas: A protein expression signature specific for benign apocrine metaplasia

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