Paracrine and gap junctional communication in breast epithelial cells: Role in diffrentiation and cancer
Abstract
Homeostasis of the mammary gland is closely regulated by systemic hormones and local factors. It is documented that the effect of systemic hormones is mediated and modulated by local diffusible factors that are communicated between the various cells of the mammary gland. Consequently, local cellular interactions, notably paracrine and gap junctional communication (GJC), play critical roles in normal function as well as dysfunction associated with cancer within the tissue context of the mammary gland. This thesis addressed the potential role of these cellular interactions in differentiation and tumor progression of human mammary epithelium using a three-dimensional (3D) cell culture. Early development of breast cancer is characterized by the presence of few neoplastic epithelial cells amidst an excess of normal epithelial structures. However, the influence of the normal epithelium on tumor progression is largely unknown. Towards this goal, I have employed a 3D paracrine interaction model of genetically matched phenotypically normal and malignant human mammary epithelial cells. The data show that differentiated glandular structures (acini) promoted tumor growth. Further, this effect is attributed to a mechanism that abrogates IL-6-mediated autocrine inhibitory pathway in malignant cells. This protection by the normal epithelium could favor the growth early stage of breast tumors. Gap junctional communication by connexins (Cxs) is considered essential for the differentiation of mammary epithelial cells mainly because of its tumor suppressor effect on breast cancer cells. However, the role of GJC in the differentiation of the normal epithelium, notably in the establishment of basoapical polarity, is largely unknown. To this end, I used a 3D cell culture system that promotes glandular (acinar) differentiation of human mammary luminal epithelial cells. Acini expressed apical Cx43, remarkably reproducing the distribution observed in vivo in breast tissue. Chemically blocking GJC or silencing Cx43 expression during differentiation resulted in marked acinar malformation. Glandular malformation was also accompanied by disruption of apical polarity as shown by the loss of the tight junction protein ZO-1 from the apical location. Interestingly, structures that lacked apical polarity were selectively induced to enter the cell cycle by mitogenic stimulation or by altering nuclear organization. These data show a novel role for Cx43 in the regulation of apical polarity, a critical feature of epithelial homeostasis. Overall, this work demonstrated the importance of cellular communication in differentiation and tumor progression of the mammary gland.
Degree
Ph.D.
Advisors
Lelievre, Purdue University.
Subject Area
Cellular biology
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