Estrogen Receptor Positive Tumor Cells Research Articles

Abstract P6-01-02: Adipose tissue from breast cancer patients with the metabolic syndrome promotes proliferation and invasion of tumor cells and influences expression of genes involved in carcinogenesis.

Abstract Background: Obesity is a public health issue of global proportions and is recognised as a risk factor for post-menopausal breast cancer. Similarly, the metabolic syndrome (MetS) is recognised as a high risk state for cancer in general. Previously we have shown that the MetS is common in postmenopausal breast cancer patients and is associated with a more aggressive tumor biology. However, the molecular mechanisms by which obesity and/or the MetS promote breast cancer remain unclear. Adipose tissue, including mammary fat, is a functionally active endocrine organ. The aims of this study were to determine whether factors secreted by mammary adipose tissue could affect tumor cell biology and to assess the effect of the MetS on this adipose depot and its subsequent effect on tumor cells. Methods: Adipose tissue from fresh mastectomy specimens was cultured in serum free media for 72 h to produce adipose conditioned media (ACM). MCF-7 and MDA-MB 231 cell lines were treated with ACM for 24–48 h. Tumor cell function was then assessed by measuring cell proliferation (BrDU assay) and cell invasion. In addition, expression of 84 genes implicated in pathways involved in carcinogenesis was examined in these cell lines following ACM treatment, using quantitative PCR arrays. Results: In the estrogen receptor (ER) positive MCF-7 cell line, ACM from MetS breast cancer patients promoted significantly greater proliferation compared to ACM from normal weight patients (203.6 ± 34.23 vs 136.8 ± 11.58%, p = 0.022). Similarly, ACM from MetS patients significantly increased invasion of MCF-7 cells compared to ACM from normal weight patients (153.4 ± 6.027 vs 126.3 ± 6.03% RFU, p = 0.006). No differences in cell proliferation or invasion between cells treated with ACM from MetS patients compared to ACM from normal weight patients were found in the ER negative MDA-MB-231 cell line. Treatment of MCF-7 cells with ACM from MetS patients resulted in significant alterations (>2 fold up/down regulation) in expression of 11 genes involved in carcinogenesis. Primarily, genes implicated in invasion/metastasis and adhesion were differentially expressed between ACM-treated cells and cells treated with control media. On the other hand, when MDA-MB-231 cells were treated with ACM from the same patients only one gene, SERPIN B5 was significantly up-regulated > 2 fold. Conclusions: These data demonstrate that factors secreted from mammary adipose tissue from metabolically unhealthy patients promote proliferation and invasion of ER positive tumor cells and influence expression of genes involved in carcinogenesis in these cells. These effects were not observed in ER negative tumor cells suggesting that they may be mediated, at least in part by the estrogen receptor. These results have provided insight into how mammary adipose tissue may act via a paracrine mechanism to influence aspects of carcinogenesis and into how the metabolic syndrome may modulate this. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-01-02.

Dormancy Signatures and Metastasis in Estrogen Receptor Positive and Negative Breast Cancer

Breast cancers can recur after removal of the primary tumor and treatment to eliminate remaining tumor cells. Recurrence may occur after long periods of time during which there are no clinical symptoms. Tumor cell dormancy may explain these prolonged periods of asymptomatic residual disease and treatment resistance. We generated a dormancy gene signature from published experimental models and applied it to both breast cancer cell line expression data as well as four published clinical studies of primary breast cancers. We found that estrogen receptor (ER) positive breast cell lines and primary tumors have significantly higher dormancy signature scores (P<0.0000001) than ER- cell lines and tumors. In addition, a stratified analysis combining all ER+ tumors in four studies indicated 2.1 times higher hazard of recurrence among patients whose tumors had low dormancy scores (LDS) compared to those whose tumors had high dormancy scores (HDS) (p<0.000005). The trend was shown in all four individual studies. Suppression of two dormancy genes, BHLHE41 and NR2F1, resulted in increased in vivo growth of ER positive MCF7 cells. The patient data analysis suggests that disseminated ER positive tumor cells carrying a dormancy signature are more likely to undergo prolonged dormancy before resuming metastatic growth. Furthermore, genes identified with this approach might provide insight into the mechanisms of dormancy onset and maintenance as well as dormancy models using human breast cancer cell lines.

Concentration of endogenous estrogens and estrogen metabolites in the NCI-60 human tumor cell lines

BackgroundEndogenous estrogens and estrogen metabolites play an important role in the pathogenesis and development of human breast, endometrial, and ovarian cancers. Increasing evidence also supports their involvement in the development of certain lung, colon and prostate cancers.MethodsIn this study we systemically surveyed endogenous estrogen and estrogen metabolite levels in each of the NCI-60 human tumor cell lines, which include human breast, central nerve system, colon, ovarian, prostate, kidney and non-small cell lung cancers, as well as melanomas and leukemia. The absolute abundances of these metabolites were measured using a liquid chromatography-tandem mass spectrometry method that has been previously utilized for biological fluids such as serum and urine.ResultsEndogenous estrogens and estrogen metabolites were found in all NCI-60 human tumor cell lines and some were substantially elevated and exceeded the levels found in well known estrogen-dependent and estrogen receptor-positive tumor cells such as MCF-7 and T-47D. While estrogens were expected to be present at high levels in cell lines representing the female reproductive system (that is, breast and ovarian), other cell lines, such as leukemia and colon, also contained very high levels of these steroid hormones. The leukemia cell line RMPI-8226 contained the highest levels of estrone (182.06 pg/106 cells) and 17β-estradiol (753.45 pg/106 cells). In comparison, the ovarian cancer cell line with the highest levels of these estrogens contained only 19.79 and 139.32 pg/106 cells of estrone and 17β-estradiol, respectively. The highest levels of estrone and 17β-estradiol in breast cancer cell lines were only 8.45 and 87.37 pg/106 cells in BT-549 and T-47D cells, respectively.ConclusionsThe data provided evidence for the presence of significant amounts of endogenous estrogens and estrogen metabolites in cell lines not commonly associated with these steroid hormones. This broad discovery of endogenous estrogens and estrogen metabolites in these cell lines suggest that several human tumors may be beneficially treated using endocrine therapy aimed at estrogen biosynthesis and estrogen-related signaling pathways.

Immunohistochemical Study of Estrogen Receptor in the Penetrating Type of Early Gastric Cancer

Abstract: The estrogen receptor was studied in a total of 42 cases of gastric carcinoma which included 14 cases of the penetrating type of early gastric carcinoma (PEN), 14 cases of the common type of early gastric carcinomas (EA) and 14 cases of the advanced gastric carcinomas (AD). An immunohistochemical study using the anti‐ER‐D5 antibody revealed that the detection of estrogen receptor‐positive tumor cells was significantly higher in the PEN group and in the AD group than in the EA group. Moreover, the incidence of estrogen receptor immunoreactivity in infiltrative and scirrhous PENs was significantly higher than that in non‐infiltrative and non‐scirrhous PENs. These results suggests that the estrogen receptor may play an important role in infiltrative proliferation and scirrhous growth in the PENs. Furthermore, the results indicated that ER immunostaining procedures applied to endoscopic biopsy specimens could be useful for the endoscopic diagnosis of PEN‐type early gastric cancer.