To better understand the possible roles and interactions of transforming growth factor-α (TGFα) and its receptor, the epidermal growth factor (EGF) receptor in human breast epithelium, we have studied the expression of TGFα and the EGF receptor in a series of normal human mammary epithelial cells derived from reduction mammoplasty before in vitro propagation, during short term proliferation in vitro, and after immortalization. Increased TGFa mRNA expression coincided with conversion of the cells to a proliferative state in vitro. After establishment, propagation, and proliferation in vitro, the cells expressed high levels of both TGFα and EGF receptor mRNAs. Addition of diverse growth inhibitory agents, including 12-O-tetradecanoylphorbol-13-acetate (TPA), TGFβ, and sodium butyrate, to one of these rapidly proliferating cell populations (no. 184) failed to reduce the expression of either TGFα or the EGF receptor. Likewise, cessation of growth associated with both senescence and confluence of the 184 cells did not result in reduced expression. However, regulation of TGFa mRNA could be demonstrated by withdrawal of EGF from the medium or by antibody-mediated blockade of the EGF receptor in 184 cells. Antibody-mediated EGF receptor blockade also results in inhibition of growth and [3H]thymidine labeling. An autoregulatory autocrine loop appears operant in proliferating breast epithelial cells. Both growth and levels of TGFa mRNA expression are controlled by binding of ligand to the EGF receptor. These studies suggest a role for the TGFα/EGF receptor pathway in normal breast cell physiology.
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