A novel lipophilic amiloride derivative efficiently kills chemoresistant breast cancer cells.

Derivatives of the potassium-sparing diuretic amiloride are preferentially cytotoxic toward tumor cells relative to normal cells, and have the capacity to target tumor cell populations resistant to currently employed therapeutic agents. However, a major barrier to clinical translation of the amilorides is their modest cytotoxic potency, with estimated IC values in the high micromolar range. Here we report the synthesis of ten novel amiloride derivatives and the characterization of their cytotoxic potency toward MCF7 (ER/PR-positive), SKBR3 (HER2-positive) and MDA-MB-231 (triple negative) cell line models of breast cancer.

Vangl-dependent Wnt/planar cell polarity signaling mediates collective breast carcinoma motility and distant metastasis.

Background: In light of the growing appreciation for the role of collective cell motility in metastasis, a deeper understanding of the underlying signaling pathways will be critical to translating these observations to the treatment of advanced cancers. Here, we examine the contribution of Wnt/planar cell polarity (Wnt/PCP), one of the non-canonical Wnt signaling pathways and defined by the involvement of the tetraspanin-like proteins Vangl1 and Vangl2, to breast tumor cell motility, collective cell invasiveness and mammary tumor metastasis.

Methods: Vangl1 and Vangl2 knockdown and overexpression and Wnt5a stimulation were employed to manipulate Wnt/PCP signaling in a battery of breast cancer cell lines representing all breast cancer subtypes, and in tumor organoids from MMTV-PyMT mice.