Mammary tumor growth and metastasis are reduced in c‐Kit mutant Sash mice

Abstract

Besides its well‐known function in allergic response, mast cell, one of the key immune cells present in tumor microenvironment, plays important roles in cancer progression. However, the functional role of mast cells in breast cancer development and metastasis is not well understood. To test the involvement of mast cells in breast cancer, we examined the effects of loss of mast cells on mammary tumor development by crossing the well‐known mast cell deficient mouse strain sash (KitW‐sh/W‐sh) with the mammary tumor transgenic mouse strain MMTV‐Polyoma Middle T antigen (PyMT). Although mammary tumor onset was not affected in the absence of mast cells, mammary growth and metastasis were reduced in PyMT/KitW‐sh/W‐sh mice compared with PyMT/wild‐type mice (WT). Histological and immunofluorescent analyses showed that tumors from PyMT/KitW‐sh/W‐sh mice showed largely differentiated morphology with reduced angiogenesis compared with MMTV‐PyMT/WT mice. Our results suggest that mast cells may promote breast cancer growth and metastasis. Agents that can block mast cells growth are potential new therapies to treat metastatic breast cancer.

Role of Mast Cells in Shaping the Tumor Microenvironment

“…Female Kit +/ W-sh and male PyMT/Kit +/W-sh mice were used to generate female PyMT/wild-type (WT) and PyMT/Kit W-sh/W-sh littermates. They found that tumor progression and further metastasis were significantly reduced in PyMT/Kit W-sh/W-sh mice when compared with PyMT/wild-type mice (WT) [61]. In a similar protocol, Bodduluri et al [62] mated ACKR2 −/− mice with Apc Min/+ mice (determined by having a mutation in the adenomatous polyposis coli gene) to generate ACKR2 −/ − Apc Min/+ .…”

Mast Cell, the Neglected Member of the Tumor Microenvironment: Role in Breast Cancer

“…In the study by He et al, mast cell-deficient mice (Kit W-sh/W-sh ), a c-Kit knockout strain, was crossed with mice that spontaneously develop breast cancer (PyMT strain). Although the number and the onset of tumors was not affected in the offspring, the size of the tumor and their metastatic potential were significantly reduced in the c-Kit-deficient mice compared with their littermate controls [ 105 ]. Moreover, histological examination of tumors revealed a marked decreased in angiogenesis, thus supporting the fact that mast cells are not as important for tumor initiation as they are for tumor progression and that their contribution is strongly due to their ability to promote tumor vascularization.…”

Progress for Immunotherapy in Inflammatory Breast Cancer and Emerging Barriers to Therapeutic Efficacy

“…Clinically there is a positive association between mast cells and favorable prognosis in invasive, non-IBC breast cancer, thought to be mediated by anti-tumor cytolytic effects via mast cell secretion of histamine and leukotrienes [ 54 ]. However, these findings are contradicted by those from other groups suggesting that mast cell-derived factors enhance breast cancer angiogenesis and metastasis [ 55 , 56 , 57 , 58 , 59 , 60 ]. These results suggest that mast cells may be highly context-dependent, corroborated by additional studies reporting that mast cell activity may differ significantly in breast cancer depending on histological grade and/or molecular subtype [ 61 , 62 ].…”