title: The molecular, cellular and clinical consequences of targeting the estrogen receptor following estrogen deprivation therapy.
abstract: During the past 20 years our understanding of the control of breast tumor development, growth and survival has changed dramatically. The once long forgotten application of high dose synthetic estrogen therapy as the first chemical therapy to treat any cancer has been resurrected, refined and reinvented as the new biology of estrogen-induced apoptosis. High dose estrogen therapy was cast aside once tamoxifen, from its origins as a failed "morning after pill", was reinvented as the first targeted therapy to treat any cancer. The current understanding of the mechanism of estrogen-induced apoptosis is described as a consequence of acquired resistance to long term antihormone therapy in estrogen receptor (ER) positive breast cancer. The ER signal transduction pathway remains a target for therapy in breast cancer despite "antiestrogen" resistance, but becomes a regulator of resistance. Multiple mechanisms of resistance come into play: Selective ER modulator (SERM) stimulated growth, growth factor/ER crosstalk, estrogen-induced apoptosis and mutations of ER. But it is with the science of estrogen-induced apoptosis that the next innovation in women's health will be developed. Recent evidence suggests that the glucocorticoid properties of medroxyprogesterone acetate blunt estrogen-induced apoptosis in estrogen deprived breast cancer cell populations. As a result breast cancer develops during long-term hormone replacement therapy (HRT). A new synthetic progestin with estrogen-like properties, such as the 19 nortestosterone derivatives used in oral contraceptives, will continue to protect the uterus from unopposed estrogen stimulation but at the same time, reinforce apoptosis in vulnerable populations of nascent breast cancer cells.
authors.affiliation: Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.affiliation: Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Philipp Y
authors.initials: PY
authors.lastname: Maximov
authors.affiliation: Institute of Chemistry, Romanian Academy, Timisoara, Romania.
authors.forename: Ramona F
authors.initials: RF
authors.lastname: Curpan
authors.affiliation: Faculty of Medicine, The University of Jordan, Amman, Jordan.
authors.forename: Balkees
authors.initials: B
authors.lastname: Abderrahman
authors.affiliation: Department of Breast Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA. Electronic address: VCJordan@mdanderson.org.
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000009:adverse effects / Q000494:pharmacology; D009154:Mutation; D009277:Nandrolone / Q000494:pharmacology / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D009277:Nandrolone; D017258:Medroxyprogesterone Acetate
keywords: Antiestrogens; Breast cancer; Estrogen receptor; Estrogen-induced apoptosis; Estrogens; Resistance