Breast cancer (Dove Medical Press) · 2026
Estrogen-Driven Breast Carcinogenesis in a Rat Model is Linked to Retroelement Activation and Inflammation and is Susceptible to Lamivudine Treatment.
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Evdokimova Valentina, Zhang Zhenbo, Ruzanov Peter, Hung Minsheng, Khoshgoo Naghmeh, Zheng Suky, Quintayo Mary Anne, Stein Lincoln D, Bayani Jane, Radvanyi Laszlo
Аннотация
BACKGROUND: Despite significant progress in treating estrogen receptor (ER)-positive breast cancer (BC), the recurrence risk remains high and mechanisms driving initial ductal tumorigenesis is unclear. Given an emerging role of LINE-1 (L1), HERV-K and other endogenous retroviral elements (EREs) in cancer, we tested the hypothesis that their expression can be induced by estrogen and blocked by treatment with lamivudine (3TC), an HIV-1 drug that can also inhibit L1 and HERV-K encoded reverse transcriptases (RTs) and ERE propagation.
METHODS: This is a preclinical study using the well-established ACI rat model of spontaneous estrogen-driven BC to examine the earliest stages of cancer development and the effects of 3TC. Rat mammary glands and peripheral blood mononuclear cells (PBMCs) were analyzed by immunohistochemistry (IHC) and RNA sequencing (RNAseq). A panel of human BC cell lines and tissue microarrays (TMAs) were assessed by RT-qPCR, immunoblotting and IHC to evaluate ERE RNA and protein expression and a potential association with the ER- and FOXA1- positive BC.
RESULTS: Development of estrogen-induced ER+ and FOXA1+ pre-invasive ductal tumors in rat mammary glands was accompanied by systemic inflammation and upregulation of ERE RNAs in mammary glands and PBMCs; these effects were attenuated by oral administration of 3TC. L1 and HERV RNAs and proteins were also detected in human BC cell lines and in tumor tissues with high ER and FOXA1 protein levels, suggesting that their expression is an intrinsic part of the ER- and FOXA1- driven oncogenic programs.
CONCLUSION: Using a rat model, our study demonstrates estrogen dependent ERE expression in pre-invasive ER+FOXA1+ mammary tumor cells and in circulating immune cells, activation of innate immune responses, and the inhibitory effects of 3TC. ERE RNAs and proteins are also highly expressed in human ER+FOXA1+ breast cancers, warranting further investigation into their functions and a potential use of 3TC as a preventive strategy for reducing a risk of cancer progression, especially in woman with ER+FOXA1+ tumors.
METHODS: This is a preclinical study using the well-established ACI rat model of spontaneous estrogen-driven BC to examine the earliest stages of cancer development and the effects of 3TC. Rat mammary glands and peripheral blood mononuclear cells (PBMCs) were analyzed by immunohistochemistry (IHC) and RNA sequencing (RNAseq). A panel of human BC cell lines and tissue microarrays (TMAs) were assessed by RT-qPCR, immunoblotting and IHC to evaluate ERE RNA and protein expression and a potential association with the ER- and FOXA1- positive BC.
RESULTS: Development of estrogen-induced ER+ and FOXA1+ pre-invasive ductal tumors in rat mammary glands was accompanied by systemic inflammation and upregulation of ERE RNAs in mammary glands and PBMCs; these effects were attenuated by oral administration of 3TC. L1 and HERV RNAs and proteins were also detected in human BC cell lines and in tumor tissues with high ER and FOXA1 protein levels, suggesting that their expression is an intrinsic part of the ER- and FOXA1- driven oncogenic programs.
CONCLUSION: Using a rat model, our study demonstrates estrogen dependent ERE expression in pre-invasive ER+FOXA1+ mammary tumor cells and in circulating immune cells, activation of innate immune responses, and the inhibitory effects of 3TC. ERE RNAs and proteins are also highly expressed in human ER+FOXA1+ breast cancers, warranting further investigation into their functions and a potential use of 3TC as a preventive strategy for reducing a risk of cancer progression, especially in woman with ER+FOXA1+ tumors.