Molecular Immunology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Molecular Mechanisms, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via GA Amadeo, Milano, Italy.
Mol Cancer Res. 2023 Jun 1;21(6):614-627. doi: 10.1158/1541-7786.MCR-22-0370.
Breast cancer is the most common type of cancer in women worldwide, with the luminal subtype being the most widespread. Although characterized by better prognosis compared with other subtypes, luminal breast cancer is still considered a threatening disease due to therapy resistance, which occurs via both cell- and non-cell-autonomous mechanisms. Jumonji domain-containing 6, arginine demethylase and lysine hydroxylase (JMJD6) is endowed with a negative prognostic value in luminal breast cancer and, via its epigenetic activity, it is known to regulate many intrinsic cancer cell pathways. So far, the effect of JMJD6 in molding the surrounding microenvironment has not been explored.Here, we describe a novel function of JMJD6 showing that its genetic inhibition in breast cancer cells suppresses lipid droplet formation and ANXA1 expression, via estrogen receptor alpha and PPARα modulation. Reduction of intracellular ANXA1 results in decreased release in the tumor microenvironment (TME), ultimately preventing M2-type macrophage polarization and tumor aggressiveness.
Our findings identify JMJD6 as a determinant of breast cancer aggressiveness and provide the rationale for the development of inhibitory molecules to reduce disease progression also through the remodeling of TME composition.
乳腺癌是全球女性最常见的癌症类型，其中腔型亚型最为普遍。尽管与其他亚型相比，腔型乳腺癌的预后较好，但由于存在细胞自主和非细胞自主的机制，其仍然被认为是一种威胁性疾病，存在治疗耐药性。组蛋白去甲基化酶 6（JMJD6）含有精氨酸脱甲基酶和赖氨酸羟化酶结构域，在腔型乳腺癌中具有负预后价值，并且通过其表观遗传活性，已知它可以调节许多内在的癌细胞途径。到目前为止，JMJD6 对周围微环境的影响尚未被探索。在这里，我们描述了 JMJD6 的一个新功能，表明其在乳腺癌细胞中的遗传抑制作用通过雌激素受体α和 PPARα的调节，抑制脂滴形成和 ANXA1 的表达。细胞内 ANXA1 的减少导致其在肿瘤微环境（TME）中的释放减少，最终防止 M2 型巨噬细胞极化和肿瘤侵袭性。
我们的发现将 JMJD6 确定为乳腺癌侵袭性的决定因素，并为开发抑制分子提供了依据，这些分子也可以通过重塑 TME 组成来减少疾病进展。
