Co-expression of epidermal growth factor receptor and transforming growth factor-α predicts worse prognosis in breast-cancer patients

Abstract

Epidermal growth factor receptor (EGF‐R) and its ligand, transforming growth factor‐α (TGF‐α), play an important role through the autocrine growth‐regulation system in several human cancers, including breast cancer. However, the clinical significance of co‐expression of EGF‐R and TGF‐α has not been elucidated. One hundred seventy‐three female patients diagnosed as invasive ductal carcinoma who had undergone a mastectomy (159 patients) or breast‐conserving surgery (14 patients) were followed up for 81 to 119 months (median 94 months) post‐operatively. Immunoreactivity for EGF‐R, TGF‐α, p53 and c‐erbB‐2 with paraffin‐embedded carcinoma tissue was investigated using labeled streptavidin‐biotin methods. Positive rates of carcinoma cells were 27%, 33%, 32% and 26% for EGF‐R, TGF‐α, p53 and c‐erbB‐2, respectively. Expression of EGF‐R only was observed in 16% (28/173), of TGF‐α only in 22% (38/173), of both EGF‐R and TGF‐α in 11% (19/173) and of neither in 51% (88/173). By univariate analysis, significant differences in overall survival and disease‐free survival were noted according to the co‐expression of EGF‐R and TGF‐α (p < 0.0001, p < 0.0001), co‐expression of EGF‐R and c‐erbB‐2 (p = 0.0029, p = 0.0028), nodal status (p = 0.0028, p = 0.0001), tumor size (p = 0.0001, p < 0.0001) and c‐erbB‐2 expression (p = 0.0034, p = 0.018), respectively. The status of p53 expression (p = 0.01), estrogen receptor (p = 0.042) and progesterone receptor (p = 0.046) showed significant differences in overall survival. According to Cox's multivariate analysis, co‐expression of EGF‐R and TGF‐α had the most significant effect on disease‐free survival (p < 0.0001) and overall survival (p < 0.0001), followed by nodal status. Co‐expression of EGF‐R and TGF‐α by immunohistochemical detection is an independent prognostic indicator, and it may be helpful for determining the group of breast‐cancer patients with an aggressive phenotype. Int. J. Cancer 89:484–487, 2000. © 2000 Wiley‐Liss, Inc.

Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin

“…In addition, similar pathways undoubtedly contribute to other biological processes and may be hijacked or corrupted during the onset and evolution of disease. Indeed, ADAM17, AREG, TGF␣ and EGFR are often upregulated in human breast cancer, with co-expression of the latter two indicating a worse prognosis (Desruisseau et al, 2004;Lendeckel et al, 2005;Umekita et al, 2000). Moreover, experimental data show that these molecules can actively contribute to the development and progression of cancer (Borrell-Pages et al, 2003;Brandt et al, 2000;Gschwind et al, 2003).…”

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

“…And so it is not surprising that each of the participants in the ADAM17-EGFR axis have also been implicated in breast cancer. ADAM17, AREG, TGFα and EGFR are often upregulated in human breast cancers, with the co-expression of TGFα and EGFR tending to forecast a worse overall prognosis [38,[94][95][96][97][98]. Moreover, experimental data show that these molecules can actively contribute to the development and progression of cancer.…”

Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis

“…The list of genes highly expressed in the INV library (Table 2) includes some genes already known to be linked to cancer, such as ADNP, implicated in maintaining cell survival (28); TGFA, which has a role in breast tumor growth and progression (29,30); CTGF, which stimulates angiogenesis (31); CCNA2, an oncogene overexpressed in liver tumors (32); SPY1, which induces cellcycle progression (33); PTPN1, an activator of the cSrc and RAS signaling pathway, amplified in ovarian cancer (34); and YKT6 (also called SNARE), which is associated with invasive and metastatic phenotypes in breast cancer (35). The list of genes highly expressed in the INV library also includes genes not previously associated with the genesis of cancer, such as CYFIP1, SNCAIP, and ANKRD10; 11 no-matching tags and 29 tags matching to ESTs or mRNAs encoding for hypothetical proteins.…”