Abnormal Expression of Cell Cycle Regulatory Proteins in Ductal and Lobular Carcinomas of the Breast

Abstract

In a previous study, we demonstrated that the G1 cell cycle checkpoint in carcinomas of the breast is frequently abrogated by loss of p16, the product of the CDKN2/INK4A gene, and, to a lesser extent, by loss of pRB, the product of the retinoblastoma gene. The purpose of the present study was to determine whether other mechanisms of cell cycle deregulation exist in breast cancers which have retained RB and p16 function. Paraffin sections of 81 invasive breast carcinomas (49 ductal, 26 lobular, 6 mixed) were reacted with monoclonal antibodies against cyclin D1 and p53, using optimized immunohistochemical staining protocols. The staining results were correlated with the expression of p16 and pRB, and with a variety of pathological parameters and DNA ploidy. Twenty-five tumors (31%) accumulated (presumably mutant) p53 and 28 (35%) overexpressed cyclin D1; 7 carcinomas (not including any pure lobular cancers) abnormally expressed both proteins. p53 accumulation correlated with nuclear, mitotic, and overall grade, but not with tumor size, lymph node involvement, or DNA ploidy. Overexpression of cyclin D1 was not associated with any of the patho-biological variables. There was an inverse correlation between loss of p16 and high levels of p53, but not cyclin D1. The G1 cell cycle checkpoint, which is controlled by RB, cyclin D1, and p16, was abrogated in 65% of carcinomas, and only p53 was abnormal in an additional 17%. The number of abnormally expressed genes correlated with mitotic activity and overall tumor grade, but not with tumor histology, size, or nodal status, suggesting that cell cycle deregulation is an early event in breast tumorigenesis. Only 18% of the carcinomas showed a normal level of expression of the four genes tested, and p16 appeared to be the most common target of cell cycle deregulation. These data point to the importance of cell cycle regulatory protein abnormalities in human breast cancer.KEY WORDS: Breast cancer, Cell cycle, Cyclin D1, Immunohistochemistry, p16, p53, Pathology. Mod Pathol 2000;13(9):945-953It is generally accepted that several pathways need to be abrogated in the genesis of a malignant neoplasm. There is an increasing body of evidence that deregulation of one or more of the cell cycle checkpoints is among the most common abnormalities in human neoplasia. We have been particularly interested in the genes controlling the late G1 restriction point. Possibly the most critical component of the latter is pRB, the product of the retinoblastoma gene. Hyperphosphorylation, and hence inactivation of pRB is catalyzed by cyclin dependent kinases (CDKs), most notably CDK4 and 6. The CDKs are activated by binding to their respective cyclins, including cyclin D1 (1). They are inhibited by CDK inhibitors including p15 INK4B and p16 INK4A (specific for CDK4/6) and p21 WAF1 . The latter, in turn, is partially under the transcriptional control of p53 (2). We recently demonstrated that abnormal expression of the genes controlling the G1 restriction point is a very common occurrence in carcinomas ...

Immunohistochemical detection and clinicopathological significance of JARID1B/KDM5B and P16 expression in invasive ductal carcinoma of the breast

“…In other human cancers, loss of p16 expression, regardless of the mechanism, appears to confer a grave prognosis, presumably due to more rapid cell growth and increased mutation rate in p16-null cells (Robinson et al, 2003). Geradts and Ingram (2000) found p16 to be the most common target of cell cycle deregulation in invasive breast carcinomas. In recent years, a separate study revealed that the p16 protein was overexpressed in primary breast cancer, and this high level of expression was an indicator of poor prognosis (Di Vinci et al, 2005).…”

“…Abnormal cell cycle regulation in breast cancer is closely related to the incidence of breast cancer, as the loss of cell cycle regulation is an early event. Abnormalities in p16, which impact the G1 phase of the cell cycle, have been observed in a majority of breast cancer patients (Geradts and Ingram, 2000).…”

Oncolytic Herpes Simplex Virus Vector Therapy of Breast Cancer in C3(1)/SV40 T-antigen Transgenic Mice

“…Whereas SV40 T-Ag is not expressed in human breast cancer, it inactivates the p53 and Rb pathways that are commonly mutated in breast cancer (51). Heterozygous female C3(1)/T-Ag develop mammary adenocarcinomas, which histologically resembles human breast cancer usually classified as infiltrating ductal carcinoma (34).…”

Different Gene Expression Patterns in Invasive Lobular and Ductal Carcinomas of the Breast

“…However, IDC and ILC share certain characteristics in gene expression. Well differentiated IDC and ILC show similar expression of some proliferation and cell cycle regulated genes, including cyclin D1, p16, p27, mdm-2, and mib-1 (Geradts and Ingram, 2000;Soslow et al, 2000), and similar bcl-2 and HIF-1␣ expression (Coradini et al, 2002).…”