title: Oestrogen receptor negativity in breast cancer: a cause or consequence?
abstract: Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of oestrogen receptor α (ERα) expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate oestrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable. To answer that, two important approaches are considered: (1) understanding the cellular origin of heterogeneity and ER negativity in breast cancers and (2) characterization of molecular regulators of endocrine resistance. Breast tumours are heterogeneous in nature, having distinct molecular, cellular, histological and clinical behaviour. Recent advancements in perception of the heterogeneity of breast cancer revealed that the origin of a particular mammary tumour phenotype depends on the interactions between the cell of origin and driver genetic hits. On the other hand, histone deacetylases (HDACs), DNA methyltransferases (DNMTs), miRNAs and ubiquitin ligases emerged as vital molecular regulators of ER negativity in breast cancers. Restoring response to endocrine therapy through re-expression of ERα by modulating the expression of these molecular regulators is therefore considered as a relevant concept that can be implemented in treating ER-negative breast cancers. In this review, we will thoroughly discuss the underlying mechanisms for the loss of ERα expression and provide the future prospects for implementing the strategies to negate ER negativity in breast cancers.
authors.affiliation: Department of Biochemistry, Molecular and Cellular Oncology Laboratory, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Vijaya Narasihma Reddy
authors.initials: VNR
authors.lastname: Gajulapalli
authors.affiliation: Department of Biotechnology, Acharya Nagarjuna University, Guntur, Andhra Pradesh 522510, India.
authors.forename: Vijaya Lakshmi
authors.initials: VL
authors.lastname: Malisetty
authors.affiliation: Department of Biochemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh 515002, India.
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Chitta
authors.affiliation: Department of Biochemistry, Molecular and Cellular Oncology Laboratory, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India manavathibsl@uohyd.ernet.in manavbrahma@gmail.com.
authors.forename: Bramanandam
authors.initials: B
authors.lastname: Manavathi
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics*; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D054875:Ubiquitination
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D035683:MicroRNAs; D006655:Histone Deacetylases
keywords: endocrine resistance; epigenetic factors; microRNAs (miRNAs); oestrogen receptor (ER)-negative breast cancer; oestrogen receptor α; ubiquitin ligases