Classical and Novel Prognostic Markers for Breast Cancer and their Clinical Significance

Abstract

The use of biomarkers ensures breast cancer patients receive optimal treatment. Established biomarkers such as estrogen receptor (ER) and progesterone receptor (PR) have been playing significant roles in the selection and management of patients for endocrine therapy. HER2 is a strong predictor of response to trastuzumab. Recently, the roles of ER as a negative and HER2 as a positive indicator for chemotherapy have been established. Ki67 has traditionally been recognized as a poor prognostic factor, but recent studies suggest that measurement of Ki67-positive cells during treatment will more effectively predict treatment efficacy for both anti-hormonal and chemotherapy. p53 mutations are found in 20-35% of human breast cancers and are associated with aggressive disease with poor clinical outcome when the DNA-binding domain is mutated. The utility of cyclin D1 as a predictor of breast cancer prognosis is controversial, but cyclin D1b overexpression is associated with poor prognosis. Likewise, overexpression of the low molecular weight form of cyclin E1 protein predicts poor prognosis. Breast cancers from BRCA1/2 carriers often show high nuclear grades, negativity to ER/PR/HER2, and p53 mutations, and thus, are associated with poor prognosis. The prognostic values of other molecular markers, such as p14(ARF), TBX2/3, VEGF in breast cancer are also discussed. Careful evaluation of these biomarkers with current treatment modality is required to determine whether their measurement or monitoring offer significant clinical benefits.

Keywords: ARF; BRCA1/2; ER; HER2; Ki67; PR; TBX2/3; VEGF; breast cancer; cyclin D1; cyclin E; molecular marker; p53; prognosis.

Figure 1.

Signaling pathways involving molecular markers for human breast cancer. The green lines show cytoplasmic and nuclear membranes. HER2/neu is an orphan receptor that can be activated by overexpression or mutation of the transactivating domain (rat neu). Overexpression of HER2/neu results in enhanced cell survival and mitogenicity and its deregulation can lead to breast tumorigenesis. VEGF shows mitogenic activity by stimulating the Ras-Raf-Mapk and PI3K pathways. Erk activation by the Ras-Raf pathway leads to activation of the cyclin D1 promoter by Fos/Jun/Ets transcription factors. Cyclin D1 makes a complex with Cdk4/6 to phosphorylate Rb and release E2F proteins that regulate G1-S transition. Both cyclins E and A2 are direct targets for activating E2Fs. Activation of the PI3K-Akt pathway results in enhanced anti-apoptotic action through inhibition of the pro-apoptosis proteins (e.g. Bad, GSK3 and the transcription factor FKHR-L1, not shown). In addition, activation of the JAK-STAT pathway by HER2 leads to cell proliferation. A major mitogenic player acting downstream of HER2 is cyclin D1. As indicated, a number of pathways lead from the receptors to enhanced activation of cyclin D1, thereby promoting cell cycle progression. Of note, cyclin D1 also interacts with the ERα to promote its transcriptional activity in Cdk-independent fashion., Dmp1 (cyclin D binding myb-like protein 1; also named Dmtf1) is a haplo-insufficient tumor suppressor that regulates the Arf-Mdm2-p53 tumor surveillance pathway.,, Cyclin D1 is a negative regulator for Dmp1: however, it synergizes with Dmp1 on the Arf promoter. BRCA1/2 proteins are directly or indirectly phosphorylated by ATM/ATR kinases in response to DNA damage, which interact with p53 to stop the cell cycle by activating the p21^Cip1/WAF1 promoter. Abbreviations: IKK, IκB kinase; Polα, DNA polymerase α; DHFR, dihydrofolate reductase; TK, thymidine kinase; TS, thymidylate synthase; PCNA, proliferating cell nuclear antigen; ER, estrogen receptor; PR, progesterone receptor; VEGF, vascular endothelial growth factor; IR, ionizing radiation; HU, hydroxyurea; ATM, ataxia-telangiectasia mutated; ATR, Ataxia telangiectasia and Rad3 related; Chk2, checkpoint homolog 2.

Figure 2.

Immunohistochemical staining of HER2, cyclin D1, and TBX2 proteins in human breast cancer samples. Human breast cancer tissues were stained for HER2 (panel a), cyclin D1 (panel b), and TBX2 proteins (panel c) with specific antibodies. For HER2: stained with A0485 (Dako, rabbit polyclonal); for cyclin D1: sc-20044 (Santa Cruz Biotech, mouse monoclonal IgG2a); and for TBX2: sc-17880 (Santa Cruz Biotech, goat polyclonal). Magnification, x40.