Caveolin-1 P132L Mutation in Human Cancers: 1 CAVeat to be Voiced

Abstract

Caveolae are 50–100 nm flask-shaped invaginations of the plasma membrane that function as membrane organizing centers and play important roles in intracellular trafficking of cellular components (eg, lipid and cholesterol) and signal transduction.1 The CAV1 gene maps to 7q31.1 and encodes the ubiquitously expressed caveolin-1, which is an essential component of caveolae. Caveolin-1 is believed to regulate the activity of a plethora of signaling molecules highly represented in caveolae, such as H-ras, c-src, and src-like kinases; endothelial nitric oxide synthase; G-proteins and membrane-associated receptors coupled to G-proteins; or tyrosine kinase receptors including epidermal growth factor receptor.1 In normal breast tissue, caveolin-1 is expressed at high levels in adipocytes, endothelial cells, fibroblasts, and myoepithelial cells of the breast.1 Initial studies have suggested that caveolin-1 would have properties consistent with those of a tumor suppressor protein.2,3,4 A dominant negative mutation of the CAV1 gene was reported to be found in up to 20% of estrogen receptor (ER)-positive breast cancers.2,4 Surprisingly, however, CAV1 knock-out mice failed to develop any tumor.1,3 Furthermore, the presence of CAV1 gene mutations could not be independently validated.5,6,7,8,9 Concurrent with the controversies about the role of CAV1 as a tumor suppressor gene, evidence of caveolin-1 as a potential oncogene has been mounting.7,8,9,10,11,12,13,14,15 In fact, multiple independent groups have reported overexpression of caveolin-1 in aggressive subtypes of cancer,10,11,13,14,15 and even CAV1 gene amplification has been documented,14,16 although this has been shown to be a rare phenomenon. Furthermore, expression of caveolin-1 in stromal cells of breast cancer has also been shown to be associated with the outcome of breast cancer patients.17,18 Despite the interest in the tumor suppressive and oncogenic functions of caveolin-1, numerous issues remain unanswered. For instance, caveolin-1 expression in normal luminal epithelial cells of normal breast lobules and ducts remains a matter of controversy, as does the existence and prevalence of the CAV1 P132L dominant-negative mutation. In this issue of The Journal of Molecular Diagnostics, Koike et al19 have addressed the question of the prevalence of the CAV1 P132L mutation in human cancer. Using three different methods for mutation detection (ie, reverse-transcriptase direct sequencing, DNA-based direct sequencing, and cycleave PCR assay), the authors failed to detect the CAV1 P132L mutation in a large series of 409 human tumors, including 139 breast cancers [114 estrogen receptor (ER)-positive and 25 ER-negative tumors] and 270 cancers from other anatomical sites (ie, gastrointestinal tract, lung, ovary, and pancreas). Taken together, the findings reported by Koike et al19 and those by others5,6,7,8,9 call into question the presence of the CAV1 P132L mutation in breast cancers and other cancer types and heat up the debate about the roles of caveolin-1 in human cancer.