# Understanding breast cancer progression as a defect in the mechanics of tissue self-organization

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $607,989

## Abstract

ABSTRACT
A progressive breakdown in the bilayered structure of the mammary gland is the hallmark of all breast cancers,
but the structural change that occurs between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma
(IDC) is of particular importance because it represents a major inflection point in risk for patients. Breast cancers
originate in the inner luminal layer of the mammary epithelium, where transformed luminal epithelial cells (LEP)
proliferate to fill the ducts and lobules in DCIS. Surprisingly, LEP in DCIS have acquired all the necessary
genetic aberrations to invade, but remain constrained within the tissue by an intact outer myoepithelial (MEP)
layer—a group of cells that forms a dynamic barrier blocking access of the in situ tumor to the basement
membrane (BM, the specialized extracellular matrix (ECM) that surrounds the mammary epithelium). Thus, we
propose that translocation of transformed LEP past the MEP layer, and not genetic mutations, is a key rate-
limiting step in progression to IDC. Here, we aim to identify the physical and molecular changes that must occur
in LEP to facilitate this structural transition. We approach this challenge through the lens of mammary epithelial
self-organization. We previously demonstrated that normal human LEP and MEP can self-organize in vitro, and
that the capacity of MEP to exclude LEP from the BM is determined by hard-wired and lineage-specific interfacial
tensions at each cell-cell and cell-ECM interface. We showed using experiments and mathematical modeling
that the LEP-ECM interface is highly unfavorable energetically compared to the MEP-ECM interface, which
prevents LEP from positioning themselves next to the BM. We hypothesize the existence of a rate-limiting and
high-energy structural intermediate during the progression of DCIS to IDC, where LEP translocate into the MEP
layer, next to the BM. We propose a statistical mechanical framework for understanding how perturbations to
the interfacial properties and dynamics of tumor cells facilitate the formation of this intermediate. Specifically, we
predict that changes to the LEP-ECM interfacial energy are a critical physical change necessary to promote
basal translocation of transformed LEP. Preliminary studies support this hypothesis: we found that a frequently
dysregulated gene—PIK3CA—disrupts self-organization when activated in LEP by rendering the LEP-ECM
interface more energetically favorable. In this proposal, we will determine whether this and other physical
changes to LEP are necessary for their basal translocation, and identify the molecular changes downstream of
PIK3CA that give rise to these physical changes. We will test our hypothesis using complementary in vitro and
in vivo experimental systems: using organoids reconstituted from human reduction mammoplasty tissues and
genetically engineered mouse models. Our long-term goal is to reveal the changes that promote and inhibit
progression from DCIS to IDC. Better physi...

## Key facts

- **NIH application ID:** 9986406
- **Project number:** 1U01CA244109-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ANDREI GOGA
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $607,989
- **Award type:** 1
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986406

## Citation

> US National Institutes of Health, RePORTER application 9986406, Understanding breast cancer progression as a defect in the mechanics of tissue self-organization (1U01CA244109-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986406. Licensed CC0.

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