Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer

Sep 24, 2026

Breast cancer is driven by estrogen signaling, with estradiol (E2) synthesized via aromatase and dependent on the rate-limiting steroidogenic acute regulatory (StAR) protein. StAR mRNA is high in hormone-dependent breast cancer cell lines, modest in triple-negative models, and minimal in non-cancerous mammary epithelial cells, while aromatase remains abundant. Transgenic mouse tumor models show elevated StAR and correlate plasma/tissue E2 with StAR rather than aromatase. Histone deacetylase inhibitors suppress StAR and E2 in tumor-derived cultures, and StAR inhibition at clinical and preclinical doses supports therapeutic relevance, positioning StAR as a diagnostic marker and target.

LanguageEnglish

CategoryHealthcare

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Reading Time45 min

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Abstract

Introduction

Article Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer Pulak R. Manna 1,*, Sabarish Ramachandran 2, Jangampalli Adi Pradeepkiran 1, Deborah Molehin 3, Isabel Castro-Piedras 3, Kevin Pruitt 3, Vadivel Ganapathy 2 and P. Hemachandra Reddy 1,4,5,6,7,8 Citation: Manna, P.R.; Ramachandran, S.; Pradeepkiran, J.A.; Molehin, D.; Castro-Piedras, I.; Pruitt, K.; Ganapathy, V.; Reddy, P.H. Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer. Int. J. Mol. Sci. 2023, 24, 758. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24010758 Academic Editors: Roberto Campagna and Valentina Pozzi Received: 30 November 2022 Revised: 21 December 2022 Accepted: 29 December 2022 Published: 1 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Internal Medicine, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX 79430, USA 2 Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX 79430, USA 3 Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX 79430, USA 4 Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, School of Medicine, 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 8 Nutritional Sciences Department, College of Human Sciences, Texas Tech University, Lubbock, TX 79409, USA * [Correspondence: pulak.manna@ttuhsc.edu](Correspondence: pulak.manna@ttuhsc.edu); Tel.: +1-806-743-3573; Fax: +1-806-743-3143 Abstract: Breast cancer (BC) is primarily triggered by estrogens, especially 17􀀌-estradiol (E2), which are synthesized by the aromatase enzyme. While all steroid hormones are derived from cholesterol, the rate-limiting step in steroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. Herein, we demonstrate that StAR mRNA expression was aberrantly high in human hormone-dependent BC (MCF7, MDA-MB-361, and T-47D), modest in hormone-independent triple negative BC (TNBC; MDA-MB-468, BT-549, and MDA-MB-231), and had little to none in non-cancerous mammary epithelial (HMEC, MCF10A, and MCF12F) cells. In contrast, these cell lines showed abundant expression of aromatase (CYP19A1) mRNA. Immunofluorescence displayed qualitatively similar patterns of both StAR and aromatase expression in various breast cells. Additionally, three different transgenic (Tg) mouse models of spontaneous breast tumors, i.e., MMTV-Neu, MMTV-HRAS, and MMTV-PyMT, demonstrated markedly higher expression of StAR mRNA/protein in breast tumors than in normal mammary tissue. While breast tumors in these mouse models exhibited higher expression of ERa, ERb, and PR mRNAs, their levels were undetected in TNBC tumors. Accumulation of E2 in plasma and breast tissues, from MMTV-PyMT and non-cancerous Tg mice, correlated with StAR, but not with aromatase, signifying the importance of StAR in governing E2 biosynthesis in mammary tissue. Treatment

FAQs

How do StAR and aromatase expression differ across hormone-dependent, triple-negative, and non-cancerous breast cells?

StAR mRNA is aberrantly high in hormone-dependent breast cancer lines, modest in triple-negative models, and little to none in non-cancerous mammary epithelial cells. In contrast, these lines show abundant aromatase (CYP19A1) mRNA expression.

What do the transgenic mouse breast tumor models reveal about StAR’s role?

Spontaneous breast tumors in MMTV-Neu, MMTV-HRAS, and MMTV-PyMT models display markedly higher StAR mRNA/protein than normal mammary tissue. E2 accumulation correlates with StAR rather than aromatase, and TNBC tumors show undetected ERa/ERb/PR levels.

How do histone deacetylase inhibitors affect StAR and E2, and why is this therapeutically relevant?

HDAC inhibitors suppress StAR and E2 levels in primary cultures of enriched breast tumor epithelial cells from MMTV-PyMT mice. In MCF7 cells, inhibition of StAR alongside E2 synthesis at clinical and preclinical doses supports StAR as a potential therapeutic target in hormone-dependent breast cancer.

Sep 24, 2026

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