Hormonal and Genetic Regulatory Events in Breast Cancer and Its Therapeutics: Importance of the Steroidogenic Acute Regulatory Protein

Pulak R Manna; Ahsen U Ahmed; Deborah Molehin; Madhusudhanan Narasimhan; Kevin Pruitt; P Hemachandra Reddy

doi:10.3390/biomedicines10061313

Hormonal and Genetic Regulatory Events in Breast Cancer and Its Therapeutics: Importance of the Steroidogenic Acute Regulatory Protein

Biomedicines. 2022 Jun 3;10(6):1313. doi: 10.3390/biomedicines10061313.

Authors

Pulak R Manna¹, Ahsen U Ahmed², Deborah Molehin³, Madhusudhanan Narasimhan⁴, Kevin Pruitt³, P Hemachandra Reddy^{1

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Affiliations

¹ Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
² Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
³ Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
⁴ Neuroscience and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
⁵ Neurology, Departments of School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
⁶ Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
⁷ Department of Speech, Language and Hearing Sciences, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.

Abstract

Estrogen promotes the development and survival of the majority of breast cancers (BCs). Aromatase is the rate-limiting enzyme in estrogen biosynthesis, and it is immensely expressed in both cancerous and non-cancerous breast tissues. Endocrine therapy based on estrogen blockade, by aromatase inhibitors, has been the mainstay of BC treatment in post-menopausal women; however, resistance to hormone therapy is the leading cause of cancer death. An improved understanding of the molecular underpinnings is the key to develop therapeutic strategies for countering the most prevalent hormone receptor positive BCs. Of note, cholesterol is the precursor of all steroid hormones that are synthesized in a variety of tissues and play crucial roles in diverse processes, ranging from organogenesis to homeostasis to carcinogenesis. The rate-limiting step in steroid biosynthesis is the transport of cholesterol from the outer to the inner mitochondrial membrane, a process that is primarily mediated by the steroidogenic acute regulatory (StAR) protein. Advances in genomic and proteomic technologies have revealed a dynamic link between histone deacetylases (HDACs) and StAR, aromatase, and estrogen regulation. We were the first to report that StAR is abundantly expressed, along with large amounts of 17β-estradiol (E2), in hormone-dependent, but not hormone-independent, BCs, in which StAR was also identified as a novel acetylated protein. Our in-silico analyses of The Cancer Genome Atlas (TCGA) datasets, for StAR and steroidogenic enzyme genes, revealed an inverse correlation between the amplification of the StAR gene and the poor survival of BC patients. Additionally, we reported that a number of HDAC inhibitors, by altering StAR acetylation patterns, repress E2 synthesis in hormone-sensitive BC cells. This review highlights the current understanding of molecular pathogenesis of BCs, especially for luminal subtypes, and their therapeutics, underlining that StAR could serve not only as a prognostic marker, but also as a therapeutic candidate, in the prevention and treatment of this life-threatening disease.

Keywords: E2 biosynthesis; HDAC inhibitors; StAR; breast cancers; estrogen; hormone receptors; therapies.

Publication types

Review

Grants and funding

This work was supported in part by National Institutes of Health grant CA155223 and Cancer Prevention Research Institute of Texas (CPRIT) Award RR140008 to K.P., and AG042178, AG047812, NS105473, AG060767, AG069333, AG066347, and R41 AG060836 to P.H.R.