TRPS1 maintains luminal progenitors in the mammary gland by repressing SRF/MRTF activity

IF 6.1 1区医学 Q1 ONCOLOGY

Breast Cancer Research Pub Date : 2024-05-03 DOI:10.1186/s13058-024-01824-7

Marie Tollot-Wegner, Marco Jessen, KyungMok Kim, Adrián Sanz-Moreno, Nadine Spielmann, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Björn von Eyss

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引用次数: 0

Abstract

The transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and is critical during puberty and pregnancy. Its function in the resting state remains however unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy adult mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. Using transcriptomic approaches, flow cytometry and functional assays, we show that TRPS1 activity is essential to maintain a functional luminal progenitor compartment. This requires the repression of both YAP/TAZ and SRF/MRTF activities. TRPS1 represses SRF/MRTF activity indirectly by modulating RhoA activity. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors intrinsically linked to mechanotransduction in the mammary gland. It may also provide new insights into the oncogenic functions of TRPS1 as luminal progenitors are likely the cells of origin of many breast cancers.

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TRPS1通过抑制SRF/MRTF的活性来维持乳腺管腔内的祖细胞

转录因子 TRPS1 是乳腺癌中一种环境依赖性癌基因。在乳腺中，TRPS1 的活性仅限于管腔群体，在青春期和妊娠期至关重要。然而，它在静息状态下的功能仍不清楚。为了评估它是否可能成为癌症治疗的靶点，我们使用条件性泛在耗竭小鼠模型研究了TRPS1在健康成人乳腺中的功能，在该模型中，长期耗竭不会影响健康。通过转录组学方法、流式细胞术和功能测定，我们发现 TRPS1 的活性对维持管腔祖细胞区的功能至关重要。这需要抑制 YAP/TAZ 和 SRF/MRTF 的活性。TRPS1 通过调节 RhoA 的活性间接抑制 SRF/MRTF 的活性。我们的研究揭示了 TRPS1 在管腔祖细胞中与乳腺机械传导有内在联系的一种迄今未被发现的功能。由于管腔祖细胞可能是许多乳腺癌的起源细胞，这项研究还可能为TRPS1的致癌功能提供新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Breast Cancer Research 医学-肿瘤学

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期刊介绍： Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.