The mammary duct is composed of two layers of epithelium, the luminal or the basal epithelium. A paracrine regulation from hormone receptor-positive luminal cells to mammary stem cells, which were recently confirmed primarily via classic Wnt4-mediated β-catenin signaling or receptor for activated NF-kB ligand (RANKL). It is much less clear what negative regulators counterbalance the effect from Wnt4 or RANKL on mammary stem cells and what the roles of these negative regulators are in breast cancer. TGFβ signaling is one of the potential negative regulators for mammary stem cells, which has been known to inhibit mammary ductal morphogenesis via TGFβR-mediated activation of SMAD2/3 in a non-canonical Wnt5A-dependent manner. We recently identified that Wnt5A is produced by luminal cells, as a negative paracrine regulator of mammary stem cells via its cognate receptor Ryk, which was supported by the basolateral secretion pattern of Wnt5A. These positive (Wnt and RANKL) and negative (TGFβ and Wnt5A) signals for mammary stem cells maintain the capacity to promote or suppress breast cancer, respectively. Wnt and RANKL contribute to different steps of mammary tumorigenesis; whereas TGFβ and Wnt5A are known to inhibit mammary tumor initiation and early progression. Curiously, since basal mammary stem cells and basal-like breast cancer (BLBC) share similar set markers and gene signatures, we determined all Wnt5A receptors and found that RYK and ROR1 are highly expressed in BLBC and their expressions predict worst outcome in BLBC patients. ROR1 is low/not present in adult tissues. Our data showed that ROR1 potentiates TGFβ-induced STAT3-oncogenic signaling without affecting SMAD2/3 activation. In addition, Wnt5A induces STAT3 activation in a ROR1-dependent manner and also activates SMAD2/3 likely via RYK- and TGFβR-mediated signaling transduction in basal B type MDA-MB-231 cells. Our central hypotheses are that ROR1 can integrate signaling transduction from non-canonical Wnt5A and TGFβ and that the collective activation of STAT3 and SMAD2/3 induces a transcriptional profile responsible for BLBC progression. As the same time we explore the mechanisms how non-canonical WNT signaling can have opposite roles in breast cancer, we have developed an immunotoxin to target ROR1 specifically in BLBC.
This project has led to the publication of a Cancer Research paper, supported by a Breast Cancer Research Grant from the Holden Comprehensive Cancer Center, and secured a F30 training grant for Nick Borcherding from NIH/NCI who is in my lab for his Ph.D. research.
- Weizhou Zhang, Wei Tan, Xuefeng Wu, Maxim Poustovoitov, Amy Strasner, Wei Li, Nicholas Borcherding, Majid Ghassemian, and Michael Karin. A NIK-IKKα module expands ErbB2-induced tumor-initiating cells by stimulating nuclear export of p27/Kip1. Cancer Cell. 2013 May 13;23(5):647-59. PMID: 23602409. PMCID: PMC3981467.
- Nicholas Borcherding, David Kusner, Ryan Kolb, Qing Xie, Wei Li, Gabriel Velez, Ryan Askeland, Ronald J. Weigel, Weizhou Zhang*. Paracrine Wnt5a signaling inhibits the expansion of tumor-initiating cells. Cancer Res. 2015 May 15;75(10):1972-82. PMID: 25769722; PMCID: PMC4433621. (*Corresponding author).