Basal but not luminal mammary epithelial cells require PI3K/mTOR signaling for Ras-driven overgrowth

Kristin A Plichta; Jessica L Mathers; Shelley A Gestl; Adam B Glick; Edward J Gunther

doi:10.1158/0008-5472.CAN-12-1635

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Basal but not luminal mammary epithelial cells require PI3K/mTOR signaling for Ras-driven overgrowth

Journal article

Open access

Peer reviewed

Basal but not luminal mammary epithelial cells require PI3K/mTOR signaling for Ras-driven overgrowth

Kristin A Plichta, Jessica L Mathers, Shelley A Gestl, Adam B Glick and Edward J Gunther

Cancer research (Chicago, Ill.), Vol.72(22), pp.5856-5866

11/15/2012

DOI: 10.1158/0008-5472.CAN-12-1635

PMCID: PMC4078248

PMID: 23010075

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Abstract

The mammary ducts of humans and mice are comprised of two main mammary epithelial cell (MEC) subtypes: a surrounding layer of basal MECs and an inner layer of luminal MECs. Breast cancer subtypes show divergent clinical behavior that may reflect properties inherent in their MEC compartment of origin. How the response to a cancer-initiating genetic event is shaped by MEC subtype remains largely unexplored. Using the mouse mammary gland, we designed organotypic three-dimensional culture models that permit challenge of discrete MEC compartments with the same oncogenic insult. Mammary organoids were prepared from mice engineered for compartment-restricted coexpression of oncogenic H-RAS(G12V) together with a nuclear fluorescent reporter. Monitoring of H-RAS(G12V)-expressing MECs during extended live cell imaging permitted visualization of Ras-driven phenotypes via video microscopy. Challenging either basal or luminal MECs with H-RAS(G12V) drove MEC proliferation and survival, culminating in aberrant organoid overgrowth. In each compartment, Ras activation triggered modes of collective MEC migration and invasion that contrasted with physiologic modes used during growth factor-initiated branching morphogenesis. Although basal and luminal Ras activation produced similar overgrowth phenotypes, inhibitor studies revealed divergent use of Ras effector pathways. Blocking either the phosphoinositide 3-kinase or the mammalian target of rapamycin pathway completely suppressed Ras-driven invasion and overgrowth of basal MECs, but only modestly attenuated Ras-driven phenotypes in luminal MECs. We show that MEC subtype defines signaling pathway dependencies downstream of Ras. Thus, cells-of-origin may critically determine the drug sensitivity profiles of mammary neoplasia.

Immunohistochemistry

ras Proteins - genetics

Diphenylamine - pharmacology

Epithelial Cells - metabolism

TOR Serine-Threonine Kinases - metabolism

ras Proteins - metabolism

Cell Growth Processes - physiology

Phosphatidylinositol 3-Kinases - metabolism

Phosphatidylinositol 3-Kinases - antagonists & inhibitors

TOR Serine-Threonine Kinases - antagonists & inhibitors

Diphenylamine - analogs & derivatives

Female

Benzamides - pharmacology

Chromones - pharmacology

Epithelial Cells - cytology

Transgenes

Morpholines - pharmacology

Mice, Transgenic

Mammary Glands, Animal - drug effects

Mammary Glands, Animal - cytology

Animals

Mammary Glands, Animal - metabolism

Mitogen-Activated Protein Kinases - antagonists & inhibitors

Mice

Mitogen-Activated Protein Kinases - metabolism

Details

Title: Subtitle: Basal but not luminal mammary epithelial cells require PI3K/mTOR signaling for Ras-driven overgrowth
Creators: Kristin A Plichta - Jake Gittlen Cancer Research Foundation, PennsylvaniaState University College of Medicine, Hershey, Pennsylvania, USA
Jessica L Mathers
Shelley A Gestl
Adam B Glick
Edward J Gunther
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.72(22), pp.5856-5866
DOI: 10.1158/0008-5472.CAN-12-1635
PMID: 23010075
PMCID: PMC4078248
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: United States
Grant note: C06 RR015428 / NCRR NIH HHS R01 CA152222 / NCI NIH HHS
Language: English
Date published: 11/15/2012
Academic Unit: Radiation Oncology
Record Identifier: 9984046918902771

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