SOX11 promotes epithelial/mesenchymal hybrid state and alters tropism of invasive breast cancer cells

Abstract

SOX11 is an embryonic mammary epithelial marker that is normally silenced prior to birth. High SOX11 levels in breast tumours are significantly associated with distant metastasis and poor outcome in breast cancer patients. Here, we show that SOX11 confers distinct features to ER-negative DCIS.com breast cancer cells, leading to populations enriched with highly plastic hybrid epithelial/mesenchymal cells, which display invasive features and alterations in metastatic tropism when xenografted into mice. We found that SOX11+DCIS tumour cells metastasize to brain and bone at greater frequency and to lungs at lower frequency compared to cells with lower SOX11 levels. High levels of SOX11 leads to the expression of markers associated with mesenchymal state and embryonic cellular phenotypes. Our results suggest that SOX11 may be a potential biomarker for breast tumours with elevated risk of developing metastases and may require more aggressive therapies.

Sox11 regulates mammary tumour-initiating and metastatic capacity in Brca1-deficient mouse mammary tumour cells

“…DOX-induced expression of SOX11 in DCIS.com cells led to increased expression of markers associated with mesenchymal state, increased size of the ALDH + /CD24 + CSC population, and increased frequency of cells expressing both luminal (K8) and basal (K14, SMA) lineage markers. Furthermore, small mammary tumours that formed from cells expressing high levels of SOX11 grew out quickly when DOX chow was replaced with normal chow, suggesting that high levels of SOX11 may keep tumours in a non-proliferative state and that proliferation occurs when SOX11 levels were lowered upon DOX withdrawal ( Oliemuller et al, 2020 ).…”

“…Previously, Oliemuller et al (2017) showed that constitutive expression of low levels of SOX11 using the CMV promoter led to enhanced invasive growth of ductal carcinoma in situ lesions. A significantly higher level of SOX11 expression was achieved using a doxycycline (DOX)-inducible EF1A promoter (Oliemuller et al, 2020). DOX-induced expression of SOX11 in DCIS.com cells led to increased expression of markers associated with mesenchymal state, increased size of the ALDH + /CD24 + CSC population, and increased frequency of cells expressing both luminal (K8) and basal (K14, SMA) lineage markers.…”

“…Sox11 is an embryonic mammary epithelial marker that is normally silent in postnatal mammary epithelial cells and is expressed in some oestrogen receptor-negative (ER−) and HER2+ breast cancers ( Zvelebil et al, 2013 ). We have recently shown that SOX11 confers features of multipotency, impairs differentiation processes and alters tropism of ER− breast cancer cells to metastatic sites ( Oliemuller et al, 2020 ). Although a number of studies have shown that Sox11 is expressed in mammary stem cells during embryonic mouse mammary development, it is not known whether it has any functional role in regulating normal embryonic mammary progenitor cells ( Chung et al, 2019 ; Makarem et al, 2013 ; Wuidart et al, 2018 ; Zvelebil et al, 2013 ).…”

Oncogenic Potential of the Dual-Function Protein MEX3A

“…The mechanism underlying the sometimes severe upregulation of MEX3 protein expression in cancer remains largely elusive. However, in mouse models of breast cancer, MEX3A upregulation was induced by SOX11 [ 53 ], a member of the SOXC transcription factors, consisting of SOX4, SOX11 and SOX12. Next to functions in neuronal development [ 56 ], especially SOX4 and SOX11 were reported to harbor substantial oncogenic potential in various malignancies [ 57 ].…”

“…So far, little is known about the transcriptional control of MEX3 expression. In the human breast cancer cell line MCF10DCIS.com, MEX3A and MEX3B could be identified among the 25 most upregulated targets due to SOX11 overexpression [53]. Sox11 belongs to the SOXC group of transcription factors highly expressed during early embryogenesis and presenting one essential embryonic mammary epithelial marker upregulated in various cancers [54].…”