Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited therapeutic options for patients at high risk of disease recurrence and metastasis. The cyclic nucleotide-degrading enzyme, phosphodiesterase 10A (PDE10), that hydrolyzes both cAMP and cGMP has been previously reported to be expressed in multiple cancers and regulates key cellular signaling pathways involved in cancer cell proliferation, survival, and maintenance of stem cell-like properties. We found that PDE10 overexpression was associated with poor relapse-free survival of TNBC patients and identified its potential as a therapeutic target for TNBC using a novel inhibitor, ADT-030. Our results showed that ADT-030 inhibited the growth of TNBC cells, reduced colony-forming efficiency and enhanced the therapeutic efficacy of paclitaxel. A TNBC mouse model demonstrated that oral administration of ADT-030 significantly suppressed syngeneic tumor growth and enhanced the antitumor efficacy of paclitaxel. ADT-030 treatment altered differentially expressed genes (DEGs), signaling pathways, and cellular processes. Overall, our findings suggest that ADT-030, as a monotherapy or in combination with standard-of-care chemotherapy, may be an effective therapeutic approach for TNBC. Further studies are warranted to better understand the oncogenic role of PDE10 in TNBC and the mechanisms by which ADT-030 modulates the tumor microenvironment (TME) and enhances chemotherapy response.

The mammary gland is a heterogeneous organ that modulates ductal morphogenesis and alveolar differentiation. Obesity is a significant risk factor for several cancers, including postmenopausal breast cancer. We and others have described an association between obesity and increased breast cancer growth. However, the effects of obesity on the mammary fat pad microenvironment (MFPME) remain understudied. Here, we investigated the effect of the Western Diet (WD) on immunocompetent female mice and on their MFPME. Our data suggest that the WD increased body, liver, and perigonadal white adipose tissue (pWAT) weight, as well as myeloid cell infiltration into these tissues. Interestingly, we did not find any significant change in CD4⁺ and CD8⁺ T cells in the liver, blood, and pWAT. NanoString data demonstrates that various cellular processes, including the complement system, innate immune system, phagocytic activity, immune metabolism, and NOD-like receptor (NLR) signaling, were upregulated in the MFPME of obese mice. RNA-Seq data suggest that WD significantly modulated MFPME physiology through regulation of gene expression, cellular processes, and signaling pathways. Further investigation is necessary to determine how WD-mediated changes in MFPME modulate breast cancer biology.