Inhibition of apoptosis in human breast cancer cells: Role in tumor progression to the metastatic state

Abstract

Reduction in apoptosis has been associated with tumor metastases and response to chemotherapy in breast cancer. We examine the influence of apoptosis status and the expression of antiapoptotic proteins Bcl-2 and Bcl-x L on metastatic progression and response to therapy in an experimental model of breast cancer. We used human breast cancer cells (MDA-MB 435, MDA-MB 468 and MCF-7) to induce orthotopic xenograft tumors in nude mice. The overexpression of Bcl-2 or Bcl-x L influenced tumorigenicity, 468 transfectants being less tumorigenic than control (p < 0.0001). Lung metastasis appeared at day 120 in animals injected with 435/Bcl-2 or 435/Bcl-x L and they showed higher metastatic activity than control 435/Neo tumors (p ‫؍‬ 0.02). In contrast, mice with 468 tumors were followed for 1 year after tumor excision, but they did not develop metastatic foci. The vast catalog of cancer cell genotypes is manifested in the wide range of alterations to cell physiology that dictate malignant growth. Moreover, the growth of tumor cell populations is determined not only by the rate of cell proliferation but also by the rate of cell death. The progression of tumors until they metastasize to distant sites and withstand the action of therapy results from cumulative changes that render tumor cells more motile and invasive as well as resistant to apoptosis. 1 Gene products controlling the balance between cell death and survival arise from an expanding family of genes, of which Bcl-2 was the first to be clearly associated with apoptosis inhibition. 2,3 Several independent signal transduction pathways leading to cell death converge in a final common effector mechanism in which Bcl-2 acts as a dominant repressor. 4 This protein, which localizes to the mitochondrial membrane, nuclear envelope and endoplasmic reticulum, 5 and Bcl-x L , a member of the Bcl-2 gene family, exert their antiapoptotic function by preventing the release of cytochrome c from mitochondria to the cytosol. 6,7 The antiapoptotic activity of these proteins may be dependent upon their interaction with other death-promoting proteins. 8 -10 Reduction in apoptosis has been associated with the development of fibrocystic changes in the breast and with an increased risk of cancer. 11 The imbalance between cell survival and apoptosis could be crucial in the progression of breast cancer, allowing the accumulation of genetic alterations. 12 High levels of Bcl-2 and Bcl-x L are frequently found in tumors, where they may have distinct biologic roles in cell survival, tumor development and drug resistance. 13 Most breast cancer cells overexpress Bcl-x L and Bcl-2, which raises the question as to which is more crucial for their survival.We identified loss of apoptosis and Bcl-2 overexpression in T 1 ductal breast carcinomas and this phenotype was associated with the likelihood of lymph node metastasis in patients 14 and with accumulated oncogene alterations. 15 Increased levels of Bcl-x L expression were found in a subset of primary human breast carcinomas, mainly in undifferent...

Endonuclease G promotes cell death of non-invasive human breast cancer cells

“…However, multiple studies demonstrated an association of an invasive phenotype of breast cancer cells with suppressed apoptosis [3][4][5]. Similar inverse correlations between invasiveness and the ability to produce an apoptotic response after cell injury were described in prostate cancer [30], colon cancer [31,32], melanoma [33], hepatocellular carcinoma [34] and other types of neoplasia.…”

“…Commonly, invasive carcinomas have less apoptosis and are more resistant to chemotherapy [3][4][5]. Several studies showed decreased apoptosis in breast cancer cells in association with cancer progression, invasiveness and metastases [3,4].…”

“…Commonly, invasive carcinomas have less apoptosis and are more resistant to chemotherapy [3][4][5]. Several studies showed decreased apoptosis in breast cancer cells in association with cancer progression, invasiveness and metastases [3,4]. Histological analysis of human breast carcinomas showed that poorly differentiated breast tumors, but not welldifferentiated breast tumors, have decreased apoptosis, which seems to be important in carcinogenesis and progression [5].…”

A cytoskeleton-based functional genetic screen identifies Bcl-xL as an enhancer of metastasis, but not primary tumor growth

“…In metastatic human breast tumor cell lines, overexpression of Bcl-xL can increase cell survival in the vasculature and enhance the formation of distant metastases (Rubio et al, 2001;Fernandez et al, 2002). Likewise, coexpression of Bcl-2 with E1a and activated Ras enhances survival of tumorigenic mouse embryo fibroblasts in the vasculature (Nikiforov et al, 1997).…”

si-RNA-Mediated Silencing of ADRBK1 Gene Attenuates Breast Cancer Cell Proliferation

“…11 In this study, lentiviral vectors were used to deliver the ADRBK1 si-RNA to MDA-MB-231 cells, which is among the best choice currently available for delivering and stably expressing si-RNA in target cells. Lentiviral vectors tend to integrate distally from promoters in introns and thereby limit the oncogenicity, and they are capable of transducing nondividing cells and specifically target the nucleus.…”