Akman, T.; Pietras, K.; Köhn-Luque, A.; Acar, A.

Cancer-associated fibroblasts (CAFs) are a central component of the tumor microenvironment that facilitate a supportive niche for cancer progression and metastasis. Experimental evidence suggests that CAFs can facilitate estrogen-independent tumor growth, thereby reducing the efficacy of anti-hormonal therapies. Understanding and quantifying the complex interactions between tumor cells, hormonal signalling, and the microenvironment are crucial for designing more effective and individualized treatment strategies. We propose a mathematical framework to explore the influence of CAFs on ER+ breast cancer progression and to evaluate strategies to mitigate their impact. We develop a system of nonlinear ordinary differential equations that substantiates the experimental observations by providing a mechanistic basis for the role of CAFs in regulating estrogen-independent growth dynamics. We then employ optimal control theory to evaluate distinct therapeutic approaches involving monotherapy or combinations of: (i) inhibition of tumor-to-CAF signaling, (ii) inhibition of CAF-to-tumor proliferative signaling, and (iii) endocrine therapy. Taken together, our results demonstrate that CAF-targeted strategies can enhance treatment efficacy across various estrogen dosing regimens. Our study provides new insights into the potential of CAF as a therapeutic target that could help to improve existing approaches for endocrine therapies.