TRPS1 acts as a context-dependent regulator of mammary epithelial cell growth/differentiation and breast cancer development

Abstract

The GATA-type zinc finger transcription factor TRPS1 has been implicated in breast cancer. However, its precise role remains unclear, as both amplifications and inactivating mutations in TRPS1 have been reported. Here, we used in vitro and in vivo loss-of-function approaches to dissect the role of TRPS1 in mammary gland development and invasive lobular breast carcinoma, which is hallmarked by functional loss of E-cadherin. We show that TRPS1 is essential in mammary epithelial cells, since TRPS1-mediated suppression of interferon signaling promotes in vitro proliferation and lactogenic differentiation. Similarly, TRPS1 expression is indispensable for proliferation of mammary organoids and in vivo survival of luminal epithelial cells during mammary gland development. However, the consequences of TRPS1 loss are dependent on E-cadherin status, as combined inactivation of E-cadherin and TRPS1 causes persistent proliferation of mammary organoids and accelerated mammary tumor formation in mice. Together, our results demonstrate that TRPS1 can function as a context-dependent tumor suppressor in breast cancer, while being essential for growth and differentiation of normal mammary epithelial cells.

TRPS1 drives heterochromatic origin refiring and cancer genome evolution

“…However, interestingly, TRPS1 silencing had limited effects on the transcriptome in MCF-7 cells (Wang et al, 2018a), and evidence is emerging to suggest a multifaceted functionality for TRPS1. Indeed, a recent report found a context-dependent regulation of TRPS1 in normal mammary epithelial cell differentiation and breast cancer development (Cornelissen et al, 2020). Clearly, the oncogenic potential of TRPS1 needs experimental validation, and the molecular mechanism underlying its pathophysiological function needs further investigation.…”

Some pleomorphic adenomas of the breast share PLAG1 rearrangements with the analogous tumour of the salivary glands

“…30 TRPS1 has been shown to play a central role in cell cycle and cancer development, 31 and also as a context-dependent tumour suppressor in breast cancer, while being essential for growth and differentiation of normal mammary epithelial cells. 32 However, the role of TRPS1in breast carcinoma is controversial. In one study, TRPS1 amplifications were associated with poor survival, 33 but in other studies the expression of TRPS1 correlated with a favourable outcome.…”

Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors

“…Clearance of Cdh1/E-cadherindeficient cells by cell death prevents tumor formation [285]. However, mouse ILC develops in compound conditional knockout GEM models, in which Cdh1 inactivation is combined with activation/inactivation of an additional oncogene or tumor suppressor gene, such as Trp53, Pten, or Pik3ca [13,[287][288][289][290][291]. Schipper et al have combined Cre recombinase-induced Cdh1 inactivation with induction of a reporter gene (GFP), which allowed to scrutinize the fate of Cdh1-deficient cells [284].…”