Differential expression of p16/p21/p27 and cyclin D1/D3, and their relationships to cell proliferation, apoptosis, and tumour progression in invasive ductal carcinoma of the breast

Abstract

In order to understand the intricate relationship of cell proliferation and apoptosis in tumour development, proliferation markers (Ki-67 and c-myc), apoptosis, cell-cycle inducers cyclin D1 and D3, and cell-cycle inhibitors p16(INK4), p21(CIP1), and p27(KIP1) were evaluated in ductal breast carcinoma. The heterogeneous nature of breast tumours provides a system by which the changes in cell-cycle genes can be explored under a wide range of proliferation and apoptotic indices. To address the above issues, immunohistochemical studies were conducted in 40 pairs of tumours and adjacent normal ductal tissues. The TUNEL method was used to identify apoptotic cells. Except for p27/KIP1, the proliferation (Ki-67, c-myc) and the apoptotic indexes together with levels of p16/INK4a, p21/CIP1, cyclin D1, and cyclin D3, were clearly elevated among tumour tissues, while absent in the adjacent normal tissues. Spearman correlation analysis indicated strong associations among apoptotic index, Ki-67, c-myc, and tumour grade. In addition, p21/CIP1 and cyclin D3 were positively correlated, while p16/INK4a, p27/KIP1, and cyclin D1 were negatively correlated with tumour grade. There was clear decoupling between p21 and p27, as well as decoupling between cyclin D1 and cyclin D3, in terms of their relationship to cell proliferation and apoptosis, indicating differential roles in tumour progression.

Cyclin D3 immunoreactivity in follicular lymphoma is independent of the t(6;14)(p21.1;q32.3) translocation or cyclin D3 gene amplification and is correlated with histologic grade and Ki‐67 labeling index

“…Since cyclin D3 is capable of promoting cell cycle progression, 1 these findings lead to the speculation that its expression may contribute to drive proliferation in normal and neoplastic follicular cells. In this regard, it is noteworthy that the association between cyclin D3 and proliferation is likely to be tumor-specific, since it has been previously reported in different types of NHL with the exception of mantle cell lymphoma, 17,34 in pancreatic adenocarcinoma, 38 melanoma 39 and oral dysplastic mucosa, 40 but not in breast carcinoma, 18 gastrointestinal stromal tumor 41 and giant cell tumor of bone. 42 Grade III FLs are biologically distinct from grade I/II FLs 13 and behave aggressively, thus requiring the same therapies as diffuse large B-cell lymphomas (DLBCLs).…”

“…10 -14 Finally, an abnormal expression of cyclin D3 has been detected by immunohistochemistry in a variety of human malignancies, including NHLs. [15][16][17][18][19] Follicular lymphoma (FL) represents one of the most common types of non-Hodgkin's lymphoma in Western world. 20 The t(14; 18) translocation occurs in most FLs, leading to the overexpression of the antiapoptotic bcl-2 protein, and thus favoring the occurrence of additional gene abnormalities in the neoplastic cells.…”

Cyclin D2 and cyclin D3 play opposite roles in mouse skin carcinogenesis

“…Abnormalities in the cyclin D2 gene have also been demonstrated, especially in testicular tumors (Sicinski et al, 1996;Houldsworth et al, 1997), as well as in a wide range of B-cell malignancies (Delmer et al, 1995). Cyclin D3 was also found overexpressed in several human cancers (Ito et al, 2001;Wong et al, 2001;Hedberg et al, 2002;Pruneri et al, 2005) such as malignancies of the thymus (Filipits et al, 2002). Consistent with these results Sicinska et al (2003) established that cyclin D3-deficient mice displayed specific defects in the development of T lymphocytes.…”

Expression of D-type cyclins in colon cancer and in cell lines from colon carcinomas

“…Indeed, overexpression of the D-type cyclins has been reported in a large number of tumours (Sicinski et al, 1996;Zhang, 1999;Zhang and Li, 1999;Florenes et al, 2000;Ebert et al, 2001;Ito et al, 2001;Wong et al, 2001). However, not all three D-type cyclins are overexpressed in the same tumour and the three cyclins are differentially linked to poor outcome of the disease.…”

“…On the other hand, cyclin D2 mRNA and protein were absent in breast cancer cell lines and primary cancer tissues, while in normal breast epithelial cells, cyclin D2 was abundantly expressed (Evron et al, 2001). Overexpression of both cyclins D1 and D3 has been observed in malignant melanomas (Florenes et al, 2000), pancreatic cancer (Ito et al, 2001) and ductal carcinoma of the breast (Wong et al, 2001). However, the linkage to prognosis was different in all these cancers.…”