Loss of expression of tropomyosin-1, a novel class II tumor suppressor that induces anoikis, in primary breast tumors

Abstract

Suppression of tropomyosins (TMs), a family of actinbinding, microfilament-associated proteins, is a prominent feature of many transformed cells. Yet it is unclear whether downregulation of TMs occur in human tumors. We have investigated the expression of tropomyosin-1 (TM1) in human breast carcinoma tissues by in situ hybridization and immunofluorescence. TM1 mRNA and protein are readily detectable in normal mammary tissue. In contrast, TM1 expression is abolished in the primary human breast tumors. Expression of other TM isoforms, however, is variable among the tumors. The consistent and profound downregulation of TM1 suggests that TM1 may be a novel and useful biomarker of mammary neoplasms. These data also support the hypothesis that suppression of TM1 expression during the malignant conversion of mammary epithelium as a contributing factor of breast cancer. In support of this hypothesis, we show that the ability to suppress malignant growth properties of breast cancer cells is specific to TM1 isoform. Investigations into the mechanisms of TM1-induced tumor suppression reveal that TM1 induces anoikis (detachment induced apoptosis) in breast cancer cells. Downregulation of TM1 in breast tumors may destabilize microfilament architecture and confer resistance to anoikis, which facilitates survival of neoplastic cells outside the normal microenvironment and promote malignant growth.

MicroRNAs and Metastasis-related Gene Expression in Egyptian Breast Cancer Patients

“…Similar to our data, others found suppression in the tumor suppressor genes, TIPM1 and TIPM3 that played a role in the malignant phenotype (Mulder et al, 1994;Yu et al, 2004). The Suppression of TPM1 has been reported in malignant cells, suggesting a role for these proteins in neoplastic transformation (Raval et al, 2003). The downregulation of TIPM1 and TIPM3 with the up-regulation of mir-21 may confirm the suppression of mir-21 and can inhibit tumor growth (Jones et al, 1999) supporting the concept that mir-21 functions as an oncogene.…”

Differential tissue-specific protein markers of vaginal carcinoma

“…In bladder carcinoma alterations in TM expression (reduced TM1, 2 and 3) seem to be an early event in bladder carcinogenesis (Pawlak et al, 2004). Similar to our findings, low expression of TM1 and TM2 has been detected in cervical carcinoma (Bae et al, 2005), of TM2 in oesophageal squamous cell carcinoma (Jazii et al, 2006) and of TM1 in breast carcinoma (Franzen et al, 1996;Raval et al, 2003). However, higher levels were found in primary breast cancer that had metastasised to the axillary lymph nodes (Franzen et al, 1996).…”

Resensitization of breast cancer cells to anoikis by Tropomyosin-1: role of Rho kinase-dependent cytoskeleton and adhesion

“…Work from this and other laboratories has identified that the tropomyosin isoform-1 (TM1), is consistently suppressed in breast cancer cell lines (Bhattacharya et al, 1990) and breast tumors (Raval et al, 2003), and is downregulated in urinary bladder tumors (Pawlak et al, 2004), suggesting that the loss of TM1 may contribute to the neoplastic transformation. Restoration of TM1 expression in several oncogene-transformed (Prasad et al, 1993(Prasad et al, , 1999Braverman et al, 1996) and spontaneously transformed breast cancer cells (Mahadev et al, 2002;Raval et al, 2003) reorganizes microfilaments, forms stress fibers in a Rho-kinase-dependent fashion (Shah et al, 2001) and suppresses the anchorage-independent growth.…”

“…Restoration of TM1 expression in several oncogene-transformed (Prasad et al, 1993(Prasad et al, , 1999Braverman et al, 1996) and spontaneously transformed breast cancer cells (Mahadev et al, 2002;Raval et al, 2003) reorganizes microfilaments, forms stress fibers in a Rho-kinase-dependent fashion (Shah et al, 2001) and suppresses the anchorage-independent growth. Further investigations have revealed that TM1 induces anoikis in breast cancer cells, and thus may suppress their malignant behavior (Mahadev et al, 2002;Raval et al, 2003).…”

“…Restoration of TM1 expression in several oncogene-transformed (Prasad et al, 1993(Prasad et al, , 1999Braverman et al, 1996) and spontaneously transformed breast cancer cells (Mahadev et al, 2002;Raval et al, 2003) reorganizes microfilaments, forms stress fibers in a Rho-kinase-dependent fashion (Shah et al, 2001) and suppresses the anchorage-independent growth. Further investigations have revealed that TM1 induces anoikis in breast cancer cells, and thus may suppress their malignant behavior (Mahadev et al, 2002;Raval et al, 2003). Since TMs stabilize actin cytoskeleton (reviewed in Cooper, 2002) and regulate actin-myosin interactions (reviewed in Marston et al, 1998), we have hypothesized that TM1-mediated cytoskeletal reorganization is critical for the antineoplastic effects of TM1 (Bharadwaj et al, 2004).…”