Abstract
Approximately 70% of invasive breast cancers have some degree of dependence on the estrogen hormone for cell proliferation and growth. These tumors have estrogen and/or progesterone receptors (ER/PR+), generally referred to as hormone receptor positive (HR+) tumors, as indicated by the presence of positive staining and varying intensity levels of estrogen and/or progesterone receptors on immunohistochemistry. Therapies that inhibit ER signaling pathways, such as aromatase inhibitors (letrozole, anastrozole, exemestane), selective ER modulators (tamoxifen), and ER down-regulators (fulvestrant), are the mainstays of treatment for hormone-receptor-positive breast cancers. However, de novo or acquired resistance to ER targeted therapies is present in many tumors, leading to disease progression. The PI3K/AKT/mTOR pathway is implicated in sustaining endocrine resistance and has become the target of many new drugs for ER+ breast cancer. This article reviews the function of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway and the various classes of PI3K pathway inhibitors that have been developed to disrupt this pathway signaling for the treatment of hormone-receptor-positive breast cancer.
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Breast Neoplasms / diagnosis
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
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Class I Phosphatidylinositol 3-Kinases / genetics
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Class I Phosphatidylinositol 3-Kinases / metabolism
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DNA Mutational Analysis
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Female
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Humans
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Mutation
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Neoplasm Recurrence, Local / diagnosis
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Neoplasm Recurrence, Local / drug therapy*
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Neoplasm Recurrence, Local / genetics
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Neoplasm Recurrence, Local / pathology
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Neoplasm Staging
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Phosphoinositide-3 Kinase Inhibitors / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Estrogen / antagonists & inhibitors
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Receptors, Estrogen / metabolism
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Receptors, Progesterone / antagonists & inhibitors
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Receptors, Progesterone / metabolism
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism
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Treatment Outcome
Substances
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Phosphoinositide-3 Kinase Inhibitors
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Receptors, Estrogen
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Receptors, Progesterone
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MTOR protein, human
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases