Regulation of estrogen receptor alpha (ERalpha) plays an important role in hormone responsiveness and growth of ER-positive breast cancer cells and tumors. ZR-75 breast cancer cells were grown under conditions of normoxia (21% O(2)) or hypoxia (1% O(2) or cobaltous chloride), and hypoxia significantly increased hypoxia-inducible factor 1alpha protein within 3 h after treatment, whereas ERalpha protein levels were dramatically decreased within 6-12 h, and this response was blocked by the proteasome inhibitor MG-132. In contrast, hypoxia induced only minimal decreases in cellular Sp1 protein and did not affect ERalpha mRNA; however, hypoxic conditions decreased basal and 17beta-estradiol-induced pS2 gene expression (mRNA levels) and estrogen response element-dependent reporter gene activity in ZR-75 cells. Although 17beta-estradiol and hypoxia induce proteasome-dependent degradation of ERalpha, their effects on transactivation are different, and this may have implications for clinical treatment of mammary tumors.
"We note, however, that genetic changes are simply one component of evolution and that intratumoral Darwinian dynamics emerge fundamentally from environmental selection forces that promote phenotypic (not genotypic) adaptations . Furthermore, we acknowledge that a large body of work exists which addresses the complex dynamics of ER expression in vitro [16,17] and in vivo (Shipitson et al. ). We embrace these works and do not suggest that phenotypic adaptation alone is sufficient explain variation in ER expression. "
[Show abstract][Hide abstract] ABSTRACT: Breast carcinoma can be classified as either Estrogen Receptor (ER) positive or negative by immunohistochemical phenotyping, although ER expression may vary from 1 to 100% of malignant cells within an ER + tumor. This is similar to genetic variability observed in other tumor types and is generally viewed as a consequence of intratumoral evolution driven by random genetic mutations. Here we view cellular evolution within tumors as a classical Darwinian system in which variations in molecular properties represent predictable adaptations to spatially heterogeneous environmental selection forces. We hypothesize that ER expression is a successful adaptive strategy only if estrogen is present in the microenvironment. Since the dominant source of estrogen is blood flow, we hypothesized that, in general, intratumoral regions with higher blood flow would contain larger numbers of ER + cells when compared to areas of low blood flow and in turn necrosis.
This study used digital pathology whole slide image acquisition and advanced image analysis algorithms. We examined the spatial distribution of ER + and ER- cells, vascular density, vessel area, and tissue necrosis within histological sections of 24 breast cancer specimens. These data were correlated with the patients ER status and molecular pathology report findings.
ANOVA analyses revealed a strong correlation between vascular area and ER expression and between high fractional necrosis and absent ER expression (R2 = 39%; p < 0.003 and R2 = 46%; p < 0.001), respectively). ER expression did not correlate with tumor grade or size.
We conclude that ER expression can be understood as a Darwinian process and linked to variations in estrogen delivery by temporal and spatial heterogeneity in blood flow. This correlation suggests strategies to promote intratumoral blood flow or a cyclic introduction of estrogen in the treatment schedule could be explored as a counter-intuitive approach to increase the efficacy of anti-estrogen drugs.
BMC Cancer 04/2014; 14(1):279. DOI:10.1186/1471-2407-14-279 · 3.36 Impact Factor
"Interestingly, ERa expression is repressed by hypoxia due to the induction of proteasomal degradation of the receptor (Cooper et al., 2004; Kurebayashi, Otsuki, Moriya, & Sonoo, 2001; Stoner et al., 2002). HIF- 1a is involved in this mechanism, but it is not yet clear how this effect is mediated. "
[Show abstract][Hide abstract] ABSTRACT: Seventy percent of breast tumors express the estrogen receptor (ER), which is generally considered to predict a better outcome relative to ER-negative tumors, as they often respond to antiestrogen therapies. During cancer progression, mammary tumors can escape from estrogen control, resulting in the acquisition of invasive properties and resistance to treatment. ER expression is a dynamic phenomenon and is finely regulated at numerous levels, including the gene, mRNA, and protein levels. As a consequence, many molecular mechanisms have been implicated in modulating ER activity and estrogen signaling in mammary cancer. In fact, one-third of ER-positive breast cancer cells do not respond to first-line endocrine therapies, and a large subset of relapsing tumors retain ER expression. Increased knowledge of these mechanisms has led to the development of better prognostic methods and targeted therapies for patients; however, additional research is still needed to improve patient survival. In this chapter, we focus on the signaling pathways leading to changes in or loss of ER activity in breast cancer progression.
"Yet, in the NKI 295 data set, PROM1 expression levels were found to be lower in ERα+ tumors than in ERα- tumors . The association of HIF-1α and PROM1 expression in ER- breast cancers is not surprising, given that hypoxia is a potent stimulator of ERα degradation [60,61]. "
[Show abstract][Hide abstract] ABSTRACT: Overexpression of the oxygen-responsive transcription factor hypoxia-inducible factor 1α (HIF-1α) correlates with poor prognosis in breast cancer patients. The mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mouse is a widely utilized preclinical mouse model that resembles human luminal breast cancer and is highly metastatic. Prior studies in which the PyMT model was used demonstrated that HIF-1α is essential to promoting carcinoma onset and lung metastasis, although no differences in primary tumor end point size were observed. Using a refined model system, we investigated whether HIF-1α is directly implicated in the regulation of tumor-initiating cells (TICs) in breast cancer.
Mammary tumor epithelial cells were created from MMTV-PyMT mice harboring conditional alleles of Hif1a, followed by transduction ex vivo with either adenovirus β-galactosidase or adenovirus Cre to generate wild-type (WT) and HIF-1α-null (KO) cells, respectively. The impact of HIF-1α deletion on tumor-initiating potential was investigated using tumorsphere assays, limiting dilution transplantation and gene expression analysis.
Efficient deletion of HIF-1α reduced primary tumor growth and suppressed lung metastases, prolonging survival. Loss of HIF-1α led to reduced expression of markers of the basal lineage (K5/K14) in cells and tumors and of multiple genes involved in the epithelial-to-mesenchymal transition. HIF-1α also enhanced tumorsphere formation at normoxia and hypoxia. Decreased expression of several genes in the Notch pathway as well as Vegf and Prominin-1 (CD133)was observed in response to Hif1a deletion. Immunohistochemistry confirmed that CD133 expression was reduced in KO cells and in tumorspheres. Tumorsphere formation was enhanced in CD133hi versus CD133neg cells sorted from PyMT tumors. Limiting dilution transplantation of WT and KO tumor cells into immunocompetent recipients revealed > 30-fold enrichment of TICs in WT cells.
These results demonstrate that HIF-1α plays a key role in promoting primary mammary tumor growth and metastasis, in part through regulation of TICs. HIF-1α regulates expression of several members of the Notch pathway, CD133 and markers of the basal lineage in mammary tumors. Our results suggest that CD133, which has not been profiled extensively in breast cancer, may be a useful marker of TICs in the PyMT mouse model. These data reveal for the first time that HIF-1α directly regulates breast TIC activity in vivo.
Breast cancer research: BCR 01/2012; 14(1):R6. DOI:10.1186/bcr3087 · 5.49 Impact Factor
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