Roles of hormone replacement therapy and iron in proliferation of breast epithelial cells with different estrogen and progesterone receptor status

Dai, Jisen; Jian, Jinlong; Bosland, Maarten C.; Frenkel, Krystyna; Bernhardt, Güenther; Huang, Xi

doi:10.1016/j.breast.2007.08.009

Cited by 36 publications

(28 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This agrees with many publications showing that progesterone alone does not induce proliferation in MCF-10A cells (9,25,51). The energy status of the cell is key in the decision to progress from the G 1 to the S phase of the cycle.…”

supporting

confidence: 82%

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

Behera

Dai

Garde

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

As an example, progesterone levels correlate with increased epithelial cell proliferation, but there is discordance between the dividing cells and the cells with nuclear progesterone receptor expression. The release of paracrine growth factors from nuclear receptor-positive cells has been postulated as a mechanism, since in vitro studies show a lack of growth effect by progesterone in breast epithelial cells lacking nuclear receptors. This study examined possible nongenomic effects of progesterone in breast epithelia by using MCF-10A cells known to lack nuclear progesterone receptor expression. Treatment for 30 -60 min with progesterone or the progestin, R5020, increased mitochondrial activity as shown by an increase in mitochondrial membrane potential (hyperpolarization) with a concordant increase in total cellular ATP. The reaction was inhibited by a specific progesterone receptor antagonist and not affected by the translation inhibitor cycloheximide. Progestin treatment inhibited apoptosis induced by activation of the FasL pathway, as shown by a decrease in sub-G 1 cell fraction during fluorescence-activated cell sorting and a decrease in caspase 3/7 levels. Progestin treatment did not alter the cell cycle over 48 h. Our study demonstrates a nongenomic action of progesterone on benign breast epithelial cells, resulting in enhanced cellular respiration and protection from apoptosis.progesterone; MCF-10A cells; mitochondria; apoptosis; cellular respiration PREVIOUS STUDIES HAVE SHOWN a discordance between the proliferative action of progesterone in the breast and the content of nuclear progesterone receptors (PR-B and PR-A) in breast epithelial cells. As examples, the mitotic rate of breast epithelial cells is greatest in the progesterone-dominant luteal phase (44). Exogenous administration of estrogen plus progestin results in greater breast epithelial proliferation than estrogen alone (15, 18). The progesterone receptor knockout (PRKO) mouse, an excellent model for the function of nuclear PR in mammary gland development, supports a proliferative role. PR-B is primarily responsible for gland development, with PRKO-B mice showing less extensive ductal development and lack of alveolar terminal end buds (7,29). In contrast to these physiological effects, very few breast epithelial cells appear to express nuclear PR. In immunocytochemical studies of human breast tissue, from 6 to 13% of ductal epithelial cells express PR (6, 37), with the two PR isoforms, B and A, typically localizing in the same cell (14). Immunocytochemical analysis of proliferation by detection of Ki67 antigen in human breast or autoradiographs of [ 3 H]thymidine incorporation in rodent mammary samples show nuclear PR-expressing cells to be nonproliferating. Adjacent cells lacking nuclear PR expression have greater mitotic activity (23). This disassociation between nuclear PR expression and proliferation led to the hypothesis that nuclear PR-expressing cells regulate proliferation of adjacent cells via the control of paracrine factors (4).This ...

show abstract

supporting

confidence: 82%

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

Behera

Dai

Garde

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

show abstract

“…S7). The tumorigenic effect of iron has been attributed to several factors, such as overproduction of ROS and free radicals through irondependent Fenton reaction, induction of oxidative responsive transcriptional factors and pro-inflammatory cytokines and iron-mediated hypoxia signaling [39][40][41][42]. Consistent with previous studies [43,44], we demonstrated that iron treatment (FAC 32 μM, similar to the mean iron concentration in our breast cancer patients) could induce about 1.9-fold increase of intracellular ROS level in MBA-MB-231 cells compared to the control (Fig.…”

Section: Iron and Il-6 Jointly Promoted Tumor Cell Growthmentioning

confidence: 99%

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Zhang

Chen

Guo

et al. 2014

Cellular Signalling

111

136

View full text Add to dashboard Cite

Iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including cancers. Burgeoning evidence indicates that the central signaling of iron homeostasis, the hepcidin-ferroportin axis, is misregulated in cancers. Nonetheless, the mechanisms of misregulated expression of iron-related genes along this signaling in cancers remain largely unknown. In the current study, we found increased levels of serum hepcidin in breast cancer patients. Reduction of hepatic hepcidin through administration of heparin restrained tumorigenic properties of breast tumor cells. Mechanistic investigation revealed that increased iron, bone morphogenetic protein-6 (BMP6) and interleukin-6 (IL-6) jointly promoted the synthesis of hepatic hepcidin. Tumor hepcidin expression was marginally increased in breast tumors relative to adjacent tissues. In contrast, tumor ferroportin concentration was greatly reduced in breast tumors, especially in malignant tumors, compared to adjacent tissues. Elevation of ferroportin concentration inhibited cell proliferation in vitro and in vivo by knocking down tumor hepcidin expression. Additionally, increased IL-6 was demonstrated to jointly enhance the tumorigenic effects of iron through enforcing cell growth. Our combined data overall deciphered the machinery that altered the hepcidin-ferroportin signaling in breast cancers. Thus, targeting the hepcidin-ferroportin signaling would represent a promising therapeutics to restrain breast cancer growth.

show abstract

“…Thus, iron promoted 83 and the chelator deferoxamine attenuated 84 formation of oxidized DNA bases produced by redox cycling of estrogens. 85 Importantly, estrogen and iron exert combined effects in stimulating proliferation of breast cancer cells in tissue culture, 86 and an iron-rich diet accelerated estrogen-mediated tumor formation in hamsters. 84 Superoxide produced by estrogen redox cycling has also been shown to mobilize iron from ferritin, which may serve as a feed-forward mechanism by which estrogens increase DNA damage.…”

Section: Iron and Breast Cancermentioning

confidence: 99%

Cellular Iron Metabolism in Prognosis and Therapy of Breast Cancer

Torti

2013

Crit Rev Oncog

View full text Add to dashboard Cite

Despite many recent advances, breast cancer remains a clinical challenge. Current issues include improving prognostic evaluation and increasing therapeutic options for women whose tumors are refractory to current frontline therapies. Iron metabolism is frequently disrupted in breast cancer, and may offer an opportunity to address these challenges. Iron enhances breast tumor initiation, growth and metastases. Iron may contribute to breast tumor initiation by promoting redox cycling of estrogen metabolites. Up-regulation of iron import and down-regulation of iron export may enable breast cancer cells to acquire and retain excess iron. Alterations in iron metabolism in macrophages and other cells of the tumor microenvironment may also foster breast tumor growth. Expression of iron metabolic genes in breast tumors is predictive of breast cancer prognosis. Iron chelators and other strategies designed to limit iron may have therapeutic value in breast cancer. The dependence of breast cancer on iron presents rich opportunities for improved prognostic evaluation and therapeutic intervention.

show abstract

Roles of hormone replacement therapy and iron in proliferation of breast epithelial cells with different estrogen and progesterone receptor status

Cited by 36 publications

References 61 publications

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

Progesterone stimulates mitochondrial activity with subsequent inhibition of apoptosis in MCF-10A benign breast epithelial cells

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Cellular Iron Metabolism in Prognosis and Therapy of Breast Cancer

Contact Info

Product

Resources

About