Abstract
Estrogen-induced apoptosis has become a successful treatment for postmenopausal metastatic, estrogen receptor-positive breast cancer. Nitric oxide involvement in the response to this endocrine treatment and its influence upon estrogen receptor-positive breast cancer progression is still unclear.Nitric oxide impact on the MCF7 breast cancer line, before and after estrogen-induced apoptosis, was investigated in 3D culture systems using unique live-cell imaging methodologies.Spheroids were established from MCF7 cells vulnerable to estrogen-induced apoptosis, before and after exposure to estrogen.Spheroids derived from estrogen-treated cells exhibited extensive apoptosis levels with downregulation of estrogen receptor expression, low proliferation rate and reduced metabolic activity, unlike spheroids derived from non-treated cells. In addition to basic phenotypic differences, these two cell cluster types are diverse in their reactions to exogenous nitric oxide.A dual effect of nitric oxide was observed in the breast cancer phenotype sensitive to estrogen-induced apoptosis. Nitric oxide, at the nanomolar level, induced cell proliferation, high metabolic activity, downregulation of estrogen receptor and enhanced collective invasion, contributing to a more aggressive phenotype. Following hormone supplementation, breast cancer 3D clusters were rescued from estrogen-induced apoptosis by these low nitric oxide-donor concentrations, since nitric oxide attenuates cell death levels, upregulates survivin expression and increases metabolic activity.Higher nitric oxide concentrations (100nM) inhibited cell growth, metabolism and promoted apoptosis. These results suggest that nitric oxide, in nanomolar concentrations, may inhibit estrogen-induced apoptosis, playing a major role in hormonal therapy. Inhibiting nitric oxide activity may benefit breast cancer patients and ultimately reduce tumor recurrence.
Highlights
Breast cancer (BC) occurs in both women and men, and its incidence increases with age
Following 5 passages in the presence of medium supplemented with E2, a dramatic cell detachment is evident, the cells grow in multilayer structures (Figure 1C) and extensive apoptosis is apparent (Figure 1D)
The biology of estrogen-induced apoptosis has created a need for therapeutic approaches to block cell survival pathways in order to augment hormoneinduced apoptosis and to provide an inexpensive targeted therapy to maintain Estrogen receptor (ER)-positive BC patients indefinitely
Summary
Breast cancer (BC) occurs in both women and men, and its incidence increases with age. Hormonal manipulation is achieved either at a cellular level by using anti-estrogens, such as tamoxifen, to compete for ER in the breast tumor, or systemically, by lowering estrogen levels in premenopausal women by the use of luteinizing hormone-releasing hormone agonists and in postmenopausal women by aromatase inhibitors that block estrogen biosynthesis in non-ovarian tissues These endocrine therapies are very effective as treatment for ER-positive BC, and for patients with early-stage disease, hormonal therapy given for five years after primary surgery markedly delays local and distant relapse and prolongs overall survival [2, 3]. Much progress has been made in understanding the molecular biology associated with secondary endocrine resistance
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