Comparative Mammary Research

Worldwide, breast cancer accounts for nearly a quarter of all cancers in women and it remains the second leading cause of cancer deaths in the US, despite intense research for over a century. Efforts to decrease its incidence and mortality are hindered by a lack in our understanding of the mechanisms involved in breast cancer initiation and pathogenesis. Interestingly, and despite the fact that the mammary gland is conserved in development and function, the natural incidence of mammary/breast cancer greatly varies among mammals – a phenomenon that remains largely unexplained. This knowledge forms the basis of our overarching aim; that a multi-species comparative approach based on mammals with a natural variation in mammary cancer incidence has the power to identify novel molecular mechanisms responsible for susceptibility or resistance to mammary cancer. In the long term, understanding the underlying molecular mechanisms of breast cancer within the context of species diversity will help define important regulatory mechanisms that will lead to the identification of breast cancer biomarkers and therapeutic targets.

We recently established an antibody-independent method to isolate and culture epithelial cells from the mammary gland of virtually any mammal, named mammosphere-derived epithelial cells (MDEC). Thus far, we have established MDEC cultures from multiple species including humans, Old World monkeys, rodents, as well as companion, agricultural, and wild, animals. This unique collection of MDEC cultures from different species allows us to study cell autonomous regulation mechanisms, both inherently as well as in response to pro-tumorigenic stimuli. For this work, we establish and use in vitro 2D cell cultures, ex vivo 3D organoid models, and in vivo xenotransplantation rodent models.

Selected publications:

1) Secreted sphingomyelins modulate low mammary cancer incidence observed in certain mammals
Ledet MM, Harman RM, Fan JC, Schmitt-Matzen EM, Diaz-Rubio ME, Zhang S, Van de Walle GR.
Scientific Reports. 2020 Nov 15;10(1):20580. doi: 10.1038/s41598-020-77639-1

2) Differential signaling pathway activation in 7,12-dimethylbenz[a] anthracene (DMBA)-treated mammary stem/progenitor cells from species with varying mammary cancer incidence.
Ledet MM, Oswald M, Anderson R, Van de Walle GR.
Oncotarget. 2018 Aug 28;9(67):32761-32774. doi: 10.18632/oncotarget.25988.

3) Conserved and variable: Understanding mammary stem cells across species.
Rauner G, Ledet MM, Van de Walle GR.
Cytometry A. 2018 Jan;93(1):125-136. doi: 10.1002/cyto.a.23190.

4) BB-Cl-Amidine as a novel therapeutic for canine and feline mammary cancer via activation of the endoplasmic reticulum stress pathway..
Ledet MM, Anderson R, Harman R, Muth A, Thompson PR, Coonrod SA, Van de Walle GR.
BMC Cancer. 2018 Apr 12;18(1):412. doi: 10.1186/s12885-018-4323-8.

5) Microvesicle-mediated Wnt/β-Catenin Signaling Promotes Interspecies Mammary Stem/Progenitor Cell Growth.
Bussche L, Rauner G, Antonyak M, Syracuse B, McDowell M, Brown AM, Cerione RA, Van de Walle GR.
J Biol Chem. 2016 Nov 18;291(47):24390-24405.

6) A Comparative Study on the In Vitro Effects of the DNA Methyltransferase Inhibitor 5-Azacytidine (5-AzaC) in Breast/Mammary Cancer of Different Mammalian Species.
Harman RM, Curtis TM, Argyle DJ, Coonrod SA, Van de Walle GR.
J Mammary Gland Biol Neoplasia. 2016 Jun;21(1-2):51-66. doi: 10.1007/s10911-016-9350-y.