Stromal Estrogen Receptor-alpha Promotes Tumor Growth by Normalizing an Increased Angiogenesis
ABSTRACT Estrogens directly promote the growth of breast cancers that express the estrogen receptor α (ERα). However, the contribution of stromal expression of ERα in the tumor microenvironment to the protumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17β-estradiol (E2) impacts the microenvironment and modulates tumor development of ERα-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density, and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERα-deficient mice, showing a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERα was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ERα-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ERα-negative cancer cells through the activation of stromal ERα (extra-hematopoietic Tie-2 positive cells), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumors, thereby preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment.
SourceAvailable from: Debarshi Roy[Show abstract] [Hide abstract]
ABSTRACT: Protein Disulfide Isomerase (PDI), an important endoplasmic reticulum-resident oxidoreductase chaperone can bind to estrogens as well as intact with its receptor proteins (i.e., estrogen receptors (ER) α and β). It has been postulated that PDI also acts as an intracellular 17β-estradiol (E2)-binding protein that transports and accumulates E2 in live cells. Drop in E2 level promotes dissociation of E2 from PDI and released in cytosol; the released E2 can augment estrogen receptor-mediated transcriptional activity and mitogenic action in cultured cells by modulating the ERβ/ERα ratio. In this study, we observed rotenone-induced damage to PDI leads to significant increase in ERβ/ERα ratio by down-regulating ERα and up-regulating ERβ. We demonstrated that nitrosative stress induced disruption of the cellular estrogenic status can be prevented through diphenyl difluoroketone (EF24, curcumin analog) intervention by protecting PDI from reactive oxygen species (ROS)-induced damage. Together, our study suggests that both PDI and EF24 can play a vital role in maintaining cellular estrogenic homeostasis.Cell Biology International 04/2014; 38(4). DOI:10.1002/cbin.10224 · 1.64 Impact Factor
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ABSTRACT: Risk-reducing salpingo-oophorectomy (RRSO) is associated with 50% reduction of BRCA1/2-associated breast cancer (BC) risk, possibly through decreased growth activity. In this pilot study, tumor characteristics and growth rates of BRCA1/2-associated primary BCs (PBCs) detected after RRSO were compared with those of PBCs originating without RRSO. From a cohort of 271 women with BRCA1/2-associated screen detected BC, we selected 20 patients with PBC detected ≥12 months after RRSO (RRSO group). Controls were 36 BRCA1/2 mutation carriers with PBC detected without RRSO (non-RRSO group) matched for age at diagnosis (± 2.5 years) and for BRCA1 or BRCA2 mutation. Pathology samples were revised for histological subtype, tumor differentiation grade, mitotic activity index (MAI), estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Tumor growth rates, expressed as tumor volume doubling times (DT), were calculated from revised magnetic resonance and mammographic images. Median age at PBC diagnosis was 52 years (range 35-67). PBCs after RRSO had lower MAIs (12 vs. 22 mitotic counts/2 mm, P = 0.02), were smaller (11 vs. 17 mm, P = 0.01), and tend to be PR-positive more often than PBCs without RRSO (38% vs. 13%, P = 0.07). Differentiation grade, ER and HER2 status were not different. Median DT was 124 days (range 89-193) in the RRSO group and 93 days (range 54-253) in the non-RRSO group (P = 0.47). BC occurring after RRSO in BRCA mutation carriers features a lower MAI, suggesting a less aggressive biological phenotype. When confirmed in larger series, this may have consequences for BC screening protocols after RRSO.Cancer biology & therapy 01/2014; 15(4). DOI:10.1158/0008-5472.SABCS13-P5-05-05 · 3.63 Impact Factor
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ABSTRACT: The purpose of the study was to explore the association of menstrual and reproductive factors with thyroid nodules in Chinese women older than 40 years of age. A questionnaire was completed by 6,571 women aged 40 years or older in a community-based epidemiological investigation of thyroid nodules conducted from June to November 2011 in Nanjing City. Thyroid nodules were measured by ultrasound. The Thyroid Imaging Reporting and Data System score was used to differentiate between benign and possibly malignant nodules. Menopausal age (>55 vs. <50 years: RR = 1.17, 95 % CI 1.00-1.34) and number of reproductive years (>40 vs. <35 years: RR = 1.12, 95 % CI 1.01-1.24) increased the risk of thyroid nodules, but were not associated with suspected malignant nodules. Women who experienced more pregnancies (≥5 vs. ≤1: RR = 2.09, 95 % CI 1.79-2.40) and abortions (≥3 vs. 0: RR = 1.61, 95 % CI 1.41-1.81) were prone to development of thyroid nodules, and more likely to form suspected malignant nodules (pregnancies, RR = 3.59, 95 % CI 1.60-7.20; abortions, RR = 2.36, 95 % CI 1.31-4.06). Furthermore, higher risks of thyroid nodules (RR = 1.36, 95 % CI 1.14-1.59) and suspected malignant nodules (RR = 2.80, 95 % CI 1.08-6.53) were observed in women who had undergone artificial compared with natural abortion. Periods of elevated estrogen and progesterone levels in women, such as pregnancy, were the key occasions for occurrence of both benign and suspiciously malignant thyroid nodules, while longer lifetime length of exposure to female sex hormones might promote the growth of thyroid nodules.Endocrine 07/2014; DOI:10.1007/s12020-014-0342-7 · 3.53 Impact Factor