[Frontiers in Bioscience 3, d944-960, September 1, 1998] |
BIOLOGICAL AND MOLECULAR BASIS OF HUMAN BREAST CANCER
Jose Russo, Xiaoqi Yang, Yun-Fu Hu, Betsy A. Bove, Yajue Huang, Ismael D.C.G. Silva, Quivo Tahin, Yuli Wu, Nadia Higgy, Abdel Zekri, and Irma H. Russo
Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
Received 12/17/97 Accepted 7/21/98
6. MOLECULAR MECHANISMS OF CELL TRANSFORMATION
6.1. Epigenetic mechanisms
The support for epigenetic mechanisms mainly stems from the fact that the efficiency of cell transformation induced by chemical carcinogens far exceeds the rate of genomic mutations imposed by the treatment (64). This notion appears to receive further support from our observations that the expression of transformed phenotypes, such as increased colony efficiency in agar methocel, was maximal shortly after exposure to chemical carcinogens and declined gradually during subsequent passage of the treated cells (Figures 7 & 8). However, the possibility remains that the cells transformed via the genetic mechanisms were gradually overwhelmed by the surrounding non-transformed cells during prolonged culture. This possibility should be examined in a suitable system in the future.
Figure 7. Survival efficiency of MCF-10F cells treated with the chemical carcinogens. MCF-10F cells were treated once (panel A) or twice (panel B) in a 7-day period. The treated cells were plated in agar methocel at every 2 passages after the treatment and allowed to grow anchorage-independently for 21 days.
Figure 8. Colony efficiency of MCF-10F cells treated with the chemical carcinogens. MCF-10F cells were treated once (panel A) or twice (panel B) in a 7-day period. The treated cells were plated in agar methocel at every 2 passages after the treatment and allowed to grow anchorage-independently for 21 days.
6.2. Genetic mechanisms
While epigenetic mechanisms of cell transformation represent a valid alternative, genetic alterations are generally perceived as the cornerstone of neoplastic development. Conceivably, neoplastic transformation occurs as a consequence of cumulative genetic alterations in regulatory mechanisms influencing cellular proliferation and/or programmed cell death or apoptosis. To delineate the molecular mechanisms responsible for cell transformation, we studied the effects of the chemical carcinogens on the expression of bcl-2, an apoptosis inhibitor (65) that is highly expressed in breast carcinomas with a low apoptotic index (66, 67), and cyclin D1, a proliferation-associated gene which is frequently amplified or overexpressed in all forms of breast carcinoma (68-72). Our results indicated that the levels of bcl-2 and cyclin D1 expression were unaffected by chemical carcinogen treatments during the initial phases of cellular transformation in vitro (14). Therefore, the role of bcl-2 and cyclin D1 in the etiology of human breast cancer, if any, appears to be subsequent to the initial stage of neoplastic transformation. The roles of other oncogenes and tumor suppressor genes in chemical carcinogenesis need to be evaluated.