PAK1 activation drives divergent resistance mechanisms to aromatase inhibition and tamoxifen in a luminal: A breast cancer model.

Breast cancer is the most frequent malignancy and the second leading cause of cancer-related mortality in women. Estrogen receptor-positive (ER+) tumors are treated with endocrine therapies such as tamoxifen or aromatase inhibitors (AI), aimed at disrupting estrogen signaling. While these therapies are initially effective, resident tumor cells can develop resistance, leading to relapse. The p21-activated kinase 1 (PAK1), a regulator of oncogenic signaling pathways, has been implicated in tamoxifen resistance. However, it remains unclear whether PAK1 also affects the response to other endocrine therapies. Here we show PAK1 activity was elevated in tamoxifen-resistant and long-term estrogen-deprived MCF7 cell lines and showed enhanced responsiveness to EGF stimulation. Inhibition of PAK1 effectively reduced cell proliferation in both models, with distinct effects on PAK1 downstream substrates. In the tamoxifen resistance context, PAK1 inhibition induced activation of the pro-apoptotic protein BAD and triggered apoptosis while proliferation-related kinases were suppressed in the estrogen-deprived model. Our findings position PAK1 as a mediator of resistance to endocrine therapies suggesting that targeting PAK1 may present a novel strategy to overcome endocrine therapy resistance in ER+ breast cancer.