Marker For Breast Cancer Progression Research Articles

Increased Expression of Leptin and the Leptin Receptor as a Marker of Breast Cancer Progression: Possible Role of Obesity-Related Stimuli

Recent in vitro studies suggested that the autocrine leptin loop might contribute to breast cancer development by enhancing cell growth and survival. To evaluate whether the leptin system could become a target in breast cancer therapy, we examined the expression of leptin and its receptor (ObR) in primary and metastatic breast cancer and noncancer mammary epithelium. We also studied whether the expression of leptin/ObR in breast cancer can be induced by obesity-related stimuli, such as elevated levels of insulin, insulin-like growth factor-I (IGF-I), estradiol, or hypoxic conditions. The expression of leptin and ObR was examined by immunohistochemistry in 148 primary breast cancers and 66 breast cancer metastases as well as in 90 benign mammary lesions. The effects of insulin, IGF-I, estradiol, and hypoxia on leptin and ObR mRNA expression were assessed by reverse transcription-PCR in MCF-7 and MDA-MB-231 breast cancer cell lines. Leptin and ObR were significantly overexpressed in primary and metastatic breast cancer relative to noncancer tissues. In primary tumors, leptin positively correlated with ObR, and both biomarkers were most abundant in G3 tumors. The expression of leptin mRNA was enhanced by insulin and hypoxia in MCF-7 and MDA-MB-231 cells, whereas IGF-I and estradiol stimulated leptin mRNA only in MCF-7 cells. ObR mRNA was induced by insulin, IGF-I, and estradiol in MCF-7 cells and by insulin and hypoxia in MDA-MB-231 cells. Leptin and ObR are overexpressed in breast cancer, possibly due to hypoxia and/or overexposure of cells to insulin, IGF-I, and/or estradiol.

Int7G24A Variant of Transforming Growth Factor-β Receptor Type I Is Associated with Invasive Breast Cancer

The transforming growth factor-beta (TGF-beta) signaling pathway has been frequently implicated in breast cancer. An intronic variant (Int7G24A) of TGF-beta receptor type I (TGFBR1) is associated with kidney and bladder cancers in our recent study. We hypothesize that this germline variant may be involved in development and progression of breast cancer. Case-control studies were designed from archived paraffin-embedded tissue specimens from the same geographic area with a homogenous ethnic population. We analyzed 223 patients (25 with preinvasive tumors and 198 with invasive and metastatic breast cancers) and 153 noncancer controls. The Int7G24A was identified by PCR-RFLP. Another germline deletion (TGFBR1*6A) and somatic mutations in the TGFBR1 were also analyzed by PCR and single-strand conformational polymorphism. The Int7G24A allele was evident in 32% of patients with preinvasive neoplasms and 48% of patients with invasive breast cancers compared with 26% controls (P = 0.00008). In addition, 11 (5.6%) homozygous Int7G24A carriers were found in patients with invasive breast cancers, whereas only 3 (2%) homozygous carriers were found in the control group. The TGFBR1*6A allele was not significantly associated with breast cancer patients and only one somatic mutation was found in 71 breast cancers. These data suggest that the germline Int7G24A variant may represent a risk factor for invasive breast cancer and a marker for breast cancer progression. A separate study with a larger sample size is warranted to validate the association of the Int7G24A with human breast cancer.

Biochemical and Biological Markers of Breast Cancer Progression

Biochemical and Biological Markers of Breast Cancer Progression

RCAS1 is associated with ductal breast cancer progression

RCAS1/EBAG9 (receptor-binding cancer antigen expressed on SiSo cells/ estrogen receptor-binding fragment-associated gene 9), an estrogen-transcribed protein, has been shown to be expressed in a wide variety of cancers, including uterine, ovarian, and lung cancer cells. Soluble and membranous RCAS1 proteins may play a role in the immune escape of tumor cells by promoting T lymphocyte inhibition of growth and apoptosis. In the present report, the presence of RCAS1 was revealed in human ductal breast cancer biopsies by immunohistochemistry. Its cytoplasmic expression was exhibited in cancer cells obtained from tumor biopsies and in breast cancer cell lines. RCAS1 significantly correlated with tumor grade. In addition, RCAS1 was identified in MCF7 culture supernatants. Those observations suggest that RCAS1 is a new marker for breast cancer progression and a possible mechanism for breast cancer immune escape.

Plasma vascular endothelial growth factor is useful in assessing progression of breast cancer post surgery and during adjuvant treatment

Vascular endothelial growth factor (VEGF) has been shown to induce angiogenesis in vivo and in vitro. However, the association of plasma VEGF with tumor histopathology in high risk groups such as African American and non-white Hispanic women with breast cancer is not well understood. There is limited information on the prognostic relevance of plasma VEGF in patients who have had surgery and adjuvant treatment for breast cancer. In this study, we measured plasma VEGF from 125 minority women with primary breast tumor removal and were completing adjuvant treatment. The control group consisted of 20 subjects without cancer. We examined the association between plasma VEGF and other tumor characteristics such as steroid hormone receptors, tumor size, regional nodes, stage, recurrence, and overall survival. Our results confirmed that plasma VEGF levels were significantly higher in breast cancer patients than normal subjects. Plasma VEGF level increased in patients with increase in tumor size, and at late stage III/IV disease. Univariate analysis showed plasma VEGF to be a significant predictor of overall survival (RR=2.5, p=0.02). Multivariate analysis showed plasma VEGF not only to be an independent predictor of overall survival (RR=4.6, p=0.02) but also of local recurrence (RR=6.0, p=0.04). Tamoxifen in combination with CMF or CAF can reduce plasma VEGF level in patients with estrogen receptor positive tumor but not in estrogen receptor negative tumor. Our findings suggest that plasma VEGF should be considered as a tumor marker for breast cancer progression, and inhibitors of angiogenesis should be factored into the treatment protocol for patients who demonstrate increase in plasma VEGF levels at any stage of the disease.

Intratumoral heterogeneity for hsp90beta mRNA levels in a breast cancer cell line.

BC-3A and BC-61 are two breast cancer cell lines that have been cloned from parental 8701-BC cells and exhibit different biosynthetic, proliferative, and invasive properties in vitro. In the attempt to search whether alterations in the profiles of gene expression could be detected, we have submitted both cytotypes to identification of differentially expressed cDNAs. In addition, steroid hormone receptor mRNA arrays and in vivo tumorigenesis of the two lines have been checked. The technique used allowed identification of changes in the expression of the 90-kD heat shock protein-beta (hsp90beta) which is prominently down-regulated in BC-61 cells. Because we have also found that these cells, which lack estrogen receptor mRNA synthesis, display a more invasive behavior in vitro and increased tumorigenesis in vivo, we propose that evaluation of hsp903 transcript levels may be taken into consideration for screening as a novel molecular marker of breast cancer progression.