Constitutive HER2 Signaling Promotes Breast Cancer Metastasis through Cellular Senescence

Abstract

Senescence, a terminal cell proliferation arrest, can be triggered by oncogenes. Oncogene-induced senescence is classically considered a tumor defense barrier. However, several findings show that, under certain circumstances, senescent cells may favor tumor progression because of their secretory phenotype. Here, we show that the expression in different breast epithelial cell lines of p95HER2, a constitutively active fragment of the tyrosine kinase receptor HER2, results in either increased proliferation or senescence. In senescent cells, p95HER2 elicits a secretome enriched in proteases, cytokines, and growth factors. This secretory phenotype is not a mere consequence of the senescence status and requires continuous HER2 signaling to be maintained. Underscoring the functional relevance of the p95HER2-induced senescence secretome, we show that p95HER2-induced senescent cells promote metastasis in vivo in a non-cell-autonomous manner. Cancer Res; 73(1); 450-8. Ó2012 AACR.

Constitutively Active ErbB2 Regulates Cisplatin-Induced Cell Death in Breast Cancer Cells via Pro- and Antiapoptotic Mechanisms

“…In congruence our findings, both expression of a truncated ErbB2 (17) and overexpression of heregulin (48) have been shown to increase p21 expression, and p53-independent regulation of p21 is well documented (13). Notably, elevated p21 expression is characteristic of senescent cells, and long-term DNErbB2 expression was demonstrated to shift MCF-7 cells toward a senescent phenotype suggested to sustain metastasis by secreting factors regulating neighboring non-senescent cells (17). The conditions in our study (48 hours DNErbB2 expression) represent an intermediate phenotype, in which cell division is largely unaffected, and the cells therefore remain chemotherapy sensitive.…”

“…2E). It may be noted that DNErbB2 expression does not increase viability under control conditions, in congruence with the known propensity of long-term DNErbB2 expression to induce a shift toward a senescent phenotype (17), see also below.…”

“…and truncated ErbB2 elicits different signaling responses (17), little is known about the specific molecular mechanisms through which DNErbB2 signaling modifies chemotherapyinduced cell death-a knowledge that could potentially lead to novel treatment strategies. Cisplatin chemotherapy, while not in widespread use in breast cancer, has recently been proposed to have clinical advantages as combination therapy in ErbB2-positive breast cancers (6)(7)(8).…”

“…Recent microarray analyses reported upregulation of the Bcl-2 family member BCL2A1, and downregulation of BCL2L11 after expression of another truncated ErbB2 variant in MCF-7 breast cancer cells (Supplementary Table S1 in ref. 17). Collectively, this shows that multiple Bcl-2 family proteins are regulated by ErbB2 signaling, making the net effect on cell death/survival balance difficult to predict.…”

“…Furthermore, these questions have, to our knowledge, not previously been addressed specifically for DNErbB2-expressing breast cancer. Notably, despite their increased motility and invasiveness, DNErbB2-expressing cells do not exhibit increased proliferation, but in fact can undergo senescence after long-term DNErbB2 expression (17); furthermore, neither full-length (16) nor truncated (18) ErbB2 confers resistance to cell death stimuli. We hypothesize that this reflects that both pro-and antiapoptotic and -proliferative pathways are upregulated by DNErbB2.…”