The role of planar cell polarity in mammary gland development and tumorigenesis

Abstract

Planar cell polarity (PCP) is a fundamental mechanism that provides directional information to ensure coordinated cellular behaviors in a group of cells. It plays a vital role in the development and function of a multitude of organs such as brain, inner ear, and skin. However, the role of PCP in mammary gland is still rudimentary. In this study, it was found that the core PCP protein Vangl2 is abundantly expressed in mouse mammary gland. And two homologues of Vangl, including Vangl1 and Vangl2, can significantly influence mammary gland morphogenesis, indicating their critical roles in this biological process. Previous studies have also revealed that PCP plays an important role in breast cancer, however, the underlying mechanism is still unclear. Breast cancer is one of the major risk factors that threaten women's health worldwide. In breast cancer patients, metastatic breast cancer has the highest mortality rate. Metastatic breast cancer, also known as stage Ⅳ breast cancer, can spread to many other organs including lung, bone, brain, etc. Risk factors such as family history, environment, age, genetic alteration (HER2, ER, TP53…) etc. may promote the metastasis of breast cancer. Although breast cancer metastasis has been extensively studied, the cellular and molecular mechanisms still remain to be elucidated. Notably, both Vangl1 and Vangl2 are highly expressed in mammary tumors and have been associated with a negative prognosis in breast cancer patients. Interestingly, it was found that genetic ablation of both Vangl1 and Vangl2 in breast cancer cells or in a spontaneous breast cancer mouse model (MMTV-PyVT) does not influence the primary tumor growth, but markedly inhibits cancer metastasis. Prior research has shown that metastasis, a lethal factor in breast cancer progression, is strongly associated with the presence of circulating tumor cell (CTC) clusters in the bloodstream. However, the factors regulating the abundance of these CTC clusters remain largely unclear. Our results suggested that Vangl1 and Vangl2 play a significant role in promoting breast cancer metastasis by promoting the formation of CTC clusters in the bloodstream. It was further found that Vangl1 and Vangl2 can maintain the localization and expression of E-cadherin in the primary tumor leading edge, which comprises the tumor epithelial cells. Additionally, it was observed alterations in mammary tumor edge architecture in both in vitro and in vivo breast cancer mouse models, marked by a reduction in laminin, a key component of the basement membrane. Collectively, our findings unveil an important function of PCP in mammary gland development and breast cancer progression, which is a potential new target for the treatment of breast cancer metastasis.