Research Highlights

Amelie Ramirez Dr.P.H.

Elevated levels of circulating and local estrogen are considered to be the primary factor contributing to obesity-associated breast cancer risk among postmenopausal women. Collaboration between Drs. Li, Huang, and Ramirez has resulted in demonstrating a novel mechanotransduction pathway that underlies the communications between the extracellular matrix, stromal hormone output, and cancer cell growth within the same microenvironment.

Local estrogens in body fat are produced primarily by adipose stromal cells (ASCs). When production of ASCs is abnormal, it can promote the development of estrogen receptor-positive (ER+) breast cancer. This research was undertaken to show that there are two opposing factors, extracellular matrix (ECM) compliance and cell contractility, that affect the estrogen output of ASCs. By combining bioengineering and molecular tools, this study investigated the impact of a mechanical phenotype on estrogen output from ASCs and the functional consequences on proliferation of ER+ breast tumor cells.

Our results demonstrate that ASCs in a collagen-based, 3-dimensional microenvironment significantly resulted in high levels of mRNA and protein of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Indeed this finding confirms the involvement of ECM compliance with the transcription machinery of estrogen production. This mechanical cue is sequentially transduced by the concerted effort of discoidin domain receptor 1, c-Jun N-terminal kinase 1, and phosphorylated JunB, which binds and activates two breast cancer-associated aromatase promoters. In contrast, elevated cell contractility caused by actin stress fiber formation dampens aromatase transcription.

To summarize, this study addressed a clinically important question in regard to the effect of the biomechanical properties of adipose tissue on its endocrine function. Our pioneering observation highlighted here demonstrates that mechanical cues received by adipose cells from the local tissue environment are key modulators to generate aberrant estrogen output, which eventually facilitates the growth of ER+ breast cancer cells.

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