Triple-Negative Breast Cancers Exploit Fat Cells to Fuel Tumor Growth

Triple-negative breast cancers (TNBCs) within fatty tissue exploit cellular channels to break down surrounding adipose tissue as a critical energy source, thus fueling tumor growth, a new study published in Nature Communications found. 1

Triple-negative breast cancer growth linked to increased adipose tissue and elevated BMI in premenopausal women. | Image Credit: @Chinnapong - stock.adobe.com.jpeg

While a variety of cancers can be found within adipose tissue or fatty tissue depots, researchers discovered that TNBCs that are estrogen/progesterone/HER2 receptor negative are reliant on fatty acid oxidization (FAO) to grow. FAO is the body’s natural process that converts fat into energy. Tumors, often found in adipose tissue, can trick the surrounding tissue into inducing lipolysis, the process of breaking down fat deposits into free fatty acids and glycerol, which the tumor then uses to fuel growth, a process known as tumorigenesis.

The mechanism involves the formation of gap junctions—intracellular channels or special connections formed between surrounding adipose cells. These channels allow for the passage of a small molecule, cyclic adenosine monophosphate (cAMP), a signaling molecule that normally triggers lipolysis, often when the body needs energy, such as during exercise, fasting, or stress. More aggressive tumors, like TNBC, have found a way to exploit these channels and cAMP to induce lipolysis in nearby fat tissue to sustain tumor growth; however, the mechanisms by which the tumors activate lipolysis remain unclear.

Previous studies have linked increased risk for TNBCs in premenopausal patients with elevated body mass index, supporting the idea that adiposity, or increased prevalence of fatty tissue, may contribute to tumorigenesis.2 In this study, researchers analyzed breast tissue samples from 46 patients with invasive breast cancer, comparing tumor tissues and normal adjacent tissue (NAT) at varying distances. When assessing for the presence of functional gap junctions between breast cancer cells, they observed that both TNBC and positive receptor (PR) cell lines formed gap junctions; however, the gap junction-dependent dyes (used to observe the transfer rate of cAMP between cell lines) in TNBC cell lines were 30 times that of the PR cell line. Researchers inferred that this finding may point toward an increased prevalence of the MYC oncogene in TNBC, a gene that plays a key role in regulating cell growth, proliferation, metabolism, and apoptosis.1

The study also highlighted the role of gap junction B3 (GJB3), a gene that encodes for the protein connexin 31 (Cx31), which is critical for forming gap junctions. Higher GJB3 levels increase the speed and prevalence of gap junctions and intercellular communication between tumor and surrounding adipose tissue cells, thus promoting faster tumor growth. Further analysis of 21 connexin genes in 771 primary human breast cancers from publicly available RNA-sequencing data from the Cancer Genome Atlas, of which 123 were in triple-negative tumors and 648 in RP tumors, revealed that the expression of GJB was greater in TN tumors when compared with PR tumors (47.2% vs 29.8%). Of the 21 connexin genes assessed, 20 had available data, and of them, 11 were significantly upregulated and found in 5 of the 7 GJB families.

To test whether disrupting these connections could slow tumor growth, researchers then used experimental inhibitors, like carbenoxolone, to block the gap junction channels. When the gap junctions are inhibited, cAMP can no longer pass from the tumor cells to adipose cells, reducing lipolysis and the availability of fatty acids for the tumor to feed on, thus slowing its growth. By downregulating GJB3, scientists were able to partially knock out Cx31, thus delaying tumor onset and reducing tumor growth.

“The present data also do not indicate that intratumor cAMP levels are greater in TN compared to RP tumors, but that elevated Cx31 in TNBC permits increased transfer of cAMP signal from tumor to adipose tumor microenvironment and increased lipolysis in tumor-adjacent adipocytes,” the study author concluded. “Further exploration of juxtacrine signaling, in particular [gap junction–] mediated intercellular communication, may be critical in understanding the tropism of metastatic cancers to adipose-rich tissue depots throughout the body.”

References

1. Williams J, Camarda R, Malkov S, et al. Tumor cell adipocyte gap junctions activate lipolysis and contribute to breast tumorigenesis. Nat Comms. Published online August 20, 2025. doi:10.1038/s41467-025-62486-3

2. Barnard ME, Martheswaran T, Van Meter M, Buys SS, Curtin K, Doherty JA. Body mass index and mammographic density in a multiracial and multiethnic population-based study. Cancer Epidemiol Biomarkers Prev. 2022;31(7):1313-1323. doi:10.1158/1055-9965.EPI-21-1249