Loss of Stromal Caveolin-! Expression and Introduction of Exogenous Biofactors Alters ECM Protein Composition and Ductal Formation in Murine Mammary Glands

Date of Award

2016

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Abigail Hielscher, PhD

Second Advisor

Charles A Daniels, MD, PhD

Third Advisor

Richard E White, PhD, FAHA

Abstract

The breast tumor microenvironment is comprised of fibroblasts, extracellular matrix (ECM), immune and endothelial cells. Of relevance is the composition and density of the ECM and cross-linking of these proteins, which contributes to tumor progression. Fibroblasts are responsible for the deposition of aberrant matrices of tumors. Loss of caveolin-1 (cav-1), a scaffolding protein of endocytotic membrane invaginations called caveolae, has been reported in fibroblasts of breast lesions. Cav-1 has also been linked to breast tumor metastasization and decreased patient surviva l time. Fibronectin (Fn), Tenascin-C (Tn-C) and collagen (Col), known to be atypically in breast cancers, and αSMA, an established marker of activated fibroblasts and known generator of tissue contractibility, were quantified in murine mammary glands to evaluate whether loss of cav-1 affects matrix homeostasis. The mammary lactiferous ducts were counted and ductal size measured to assess the effect of cav-1 on mammary gland architecture. Simulating de novo tumorigenesis, filtered, conditioned medium from either normal or malignant breast epithelial cell cultures was injected in murine mammary glands. Here, we show that the expressions of all three stromal proteins and αSMA were elevated in cav-1 deficient tissues compared to wild type tissues. Cav-1 -/-glands also demonstrated increased number of ducts and increased duct stromal size. Furthermore, loss of cav-1 expression contributed to greater increases of αSMA, Col, Fn, and Tn-C expressions reacting to malignant bioactive factors compared to wild type tissues. Cav-1 deficient glands alone demonstrated aberrant matrix alterations in response to normal bioactive factors. Ductal counts were also elevated drastically following introduction of any bioactive factors in cav-1 deficient glands compared wild type glands. These data demonstrate that cav-1 expression is directly linked to increased expression of ECM proteins and anomalous development of lactiferous ducts. Our findings highlight the need for future studies to elucidate the potential role of the loss of cav-1 in prompting tumor initiation and progression.

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