Caveolin-1, mammary stem cells, and estrogen-dependent breast cancers.
Estrogen exposure is considered a significant risk factor for breast cancer development. Estrogen receptor (ER) alpha is expressed at low levels in normal epithelia, and its expression is dramatically up-regulated as transformation progresses during mammary hyperplasia and adenocarcinoma development. The mechanism(s) driving ERalpha up-regulation during mammary tumorigenesis remains unclear. Caveolin-1 (Cav-1) is the structural protein of plasmalemmal invaginations, termed caveolae, which functions as a tumor suppressor gene. Interestingly, Cav-1 dominant-negative mutations are exclusively found in ERalpha-positive breast cancer samples. In support of these clinical findings, ERalpha expression is increased in Cav-1 (-/-) null mammary epithelia, and estrogen stimulation further enhances the growth of Cav-1-deficient three-dimensional epithelial structures. These phenotypes correlate with augmented levels of cyclin D1. In addition, Cav-1 gene inactivation induces the accumulation of a cell population with the characteristics of adult mammary stem cells. Primary cultures of Cav-1 (-/-) mammary epithelial cells exhibit premalignant changes, such as abnormal lumen formation, epidermal growth factor-independent growth, defects in cell substrate attachment, and increased cell invasiveness. Thus, Cav-1 gene inactivation promotes premalignant alterations in mammary epithelia and induces increased ERalpha expression levels and the up-regulation of cyclin D1. As tumor formation is a multihit process, Cav-1 mutations that occur during the early stages of mammary transformation may be a critical upstream/initiating event leading to increased ERalpha levels.
Sotgia
Federica
F
Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Rui
Hallgeir
H
Bonuccelli
Gloria
G
Mercier
Isabelle
I
Pestell
Richard G
RG
Lisanti
Michael P
MP
D053687:Adult Stem Cells / Q000473:pathology*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D006801:Humans; D008321:Mammary Glands, Animal / Q000473:pathology*; D042361:Mammary Glands, Human / Q000473:pathology*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000473:pathology
D051242:Caveolin 1; D047628:Estrogen Receptor alpha