miR-203 drives breast cancer cell differentiation

Abstract

Breast cancer; Cell differentiation

Cáncer de mama; Diferenciación celular

Càncer de mama; Diferenciació cel·lular

A hallmark of many malignant tumors is dedifferentiated (immature) cells bearing slight or no resemblance to the normal cells from which the cancer originated. Tumor dedifferentiated cells exhibit a higher capacity to survive to chemo and radiotherapies and have the ability to incite tumor relapse. Inducing cancer cell differentiation would abolish their self-renewal and invasive capacity and could be combined with the current standard of care, especially in poorly differentiated and aggressive tumors (with worst prognosis). However, differentiation therapy is still in its early stages and the intrinsic complexity of solid tumor heterogeneity demands innovative approaches in order to be efficiently translated into the clinic. We demonstrate here that microRNA 203, a potent driver of differentiation in pluripotent stem cells (ESCs and iPSCs), promotes the differentiation of mammary gland tumor cells. Combining mouse in vivo approaches and both mouse and human-derived tridimensional organoid cultures, we report that miR-203 influences the self-renewal capacity, plasticity and differentiation potential of breast cancer cells and prevents tumor cell growth in vivo. Our work sheds light on differentiation-based antitumor therapies and offers miR-203 as a promising tool for directly confronting the tumor-maintaining and regeneration capability of cancer cells.

This work has been in part financed by the crowdfunding project “Match point against breast cancer” (PRECIPITA PR242, 2019; FECYT; Spanish Ministry of Science and Innovation, MICINN, led by MS-R) and donations to Asociación Española contra el Cáncer (AECC). The work has been funded also by the Comunidad de Madrid (Y2020/BIO-6519 and S2022/BMD-7437) to MM, the Spanish Ministry of Science and Innovation through CNS2022-135364 to MS-R and PID2021-128726 to MM and the Spanish Ministry of Economy and Competitiveness by Instituto de Salud Carlos III (ISC III) through PI20/00590 to CS and co-funded by the European Union. MS-R was supported by AECC (AIOA120833SALA and INVES18005SALA), a Juan de la Cierva Incorporación and a Ramón y Cajal contract (RYC2020-028929-I, from the MICINN, FSE/ Agencia Estatal de Investigación). NGM-I was supported by AECC (PRDMA19003GARC).